LOU064 for treating multiple sclerosis

Abstract

To provide effective treatment of multiple sclerosis (MS).SOLUTION: The present invention provides LOU064 for use in the treatment of multiple sclerosis or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to LOU064 or a combination thereof for use in the effective treatment of multiple sclerosis (MS). relates to pharma- ceutically acceptable salts thereof. [Background technology]

[0002] Multiple sclerosis (MS) is a central nervous system disease characterized by inflammation, demyelination, and axonal / neuronal destruction. It is a chronic, immune-mediated disease of the immune system that ultimately leads to severe disability. However, a variety of disease-modifying therapies (DMTs) are available that usually slow the progression of the disease. .

[0003] Most disease-modifying therapies for MS traditionally work via T cell-based mechanisms However, a growing body of data indicates that these DMTs act against B cells. Common themes include the development of memory cells or structures Promotion of naive B cells, but not stromal blasts (alemtuzumab); anti-inflammatory B cell cytokines shift towards pathologic (beta-interferon, glatiramer acetate, fingolimod); Increase in B-reg (beta interferon, glatiramer acetate, fingolimod and fentanyl) Dimethylmalate: Class II MHC expression on B cells required for antigen presentation and costimulation. Reduction of excitatory molecules (beta interferon and dimethyl fumarate); in lymphoid organs B cell sequestration (fingolimod); blocking VLA-4-mediated B cell trafficking to the CNS ( natalizumab); or direct cytolysis of B cells (alemtuzumab, teriflunomide, mitoxin Greenfield et al., Ann. Neurol. .2018 January;83(1):13-26

[0004] These DMTs usually significantly reduce relapse rates and MRI disease activity, and therefore delay the time to disability progression, but generally, (severe) adverse events are more frequent in these D For example, natalizumab may be associated with the prevention of fatal opportunistic infections (i.e. , progressive multifocal leukoencephalopathy, or PML), but some oral DMTs are subject to S1P-related safety risks, e.g. bradyarrhythmia at the initiation of treatment, macular edema , hypertension, and elevated hepatic transaminases.

[0005] Other treatment options for patients with MS are ofatumumab, ocrelizumab, rituximab, and obitinib. Monoclonal antibodies that target CD20-expressing B cells, such as nutuzumab and ublituximab, Nonspecific depletion of B cells by administration of anti-B cell antibodies. Torke, S. and Weber ,MS(2020),Expert Opinion on Investigat See, ional Drugs, 29:10, 1143-1150.

[0006] However, long-term studies have shown that increasing lifetime doses of B cell depleting agents result in severe immune system damage. It is emphasized that essential functions may be impaired.

[0007] Nevertheless, the long-term effects of sustained immunosuppressive therapy, such as impaired humoral response, remain unclear. Considering this, the potential of the drug to control pathogenic B cells that drive MS, particularly in patients with MS, would give physicians flexibility in their treatment regimens. Sustainable and flexible approaches to managing climate change are needed.

[0008] Recently, a novel strategy to achieve this goal has been developed, which involves the use of Bruton's tyrosine kinase (BTK). Therapeutic inhibition of K) has been proposed.

[0009] BTK is an enzyme centrally involved in B cell receptor (BCR) signaling and is BTK is essential for B cell maturation and is thought to play a key role in mediating BCR signaling. However, Fc receptor (FcR) and Toll-like receptor (TLR) signaling have been reported. It has subsequently been shown to be involved in other pathways, as well as in the production of reactive oxygen species (ROS). BTK belongs to the TEC (tyrosine kinase expressed in hepatocellular carcinoma) family of kinases. Expression of members of the TEC family of kinases is primarily restricted to the hematopoietic system.

[0010] BTK is essential for normal B cell development and maturation. Absence of BTK results in, e.g. In patients with X-linked agammaglobulinemia (XLA), peripheral B cells and plasma cells are almost completely In contrast, a significant lack of circulating immunoglobulins has been demonstrated, resulting in very low levels of circulating immunoglobulins. In xid mice, peripheral B cell maturation is specifically arrested, whereas bone marrow (BM) generation is not. The number of circulating pre-B cells is normal. BTK inhibits the IL-7-driven proliferation of large circulating pre-B cells. It regulates proliferation and promotes progression to small resting pre-B cells. It is important for B cell progression. BTK then mediates the expression of the first immunoglobulin chains and the B Finally, BTK regulates BCR-mediated B cell activation. These cells are involved in the activation of endothelial cells and eventual terminal differentiation into memory cells or plasma cells.

[0011] Thus, without wishing to be bound by any theory, it is believed that IL-1 is involved in the maturation of B cells. BTK inhibitors, which block a key enzyme, could inhibit pathogenic B cells in diseases like MS. This will be the case.

[0012] To date, several BTK inhibitors have been developed and are being used to treat several diseases. Therefore, ibrutinib (Imbruvica) is being tested in patients with chronic lymphocytic Approved for the treatment of chronic leukemia (CLL), Waldenstrom's macroglobulinemia It is used in the treatment of mantle cell lymphoma (MCL), marginal zone lymphoma, and chronic graft-versus-host disease. It is a second-line treatment. Also, for the treatment of MCL, acalabrutinib (Calquence) and zanubrutinib (Brukinsa). Tirabrutinib, as well as the new compound ONO-4059 (Tirabrutinib), HM 71224 (Poseltinib) and ABBV-105 (Upadacitinib) Currently, therapies are being developed to treat B cell malignancies and / or autoimmune diseases, such as rheumatoid arthritis (RA), rheumatoid arthritis (SH), and rheumatoid arthritis (RHA). Its efficacy in Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE) is being tested.

[0013] To date, the BTK inhibitors evobrutinib, trebrutinib, and fenebrutinib have It is currently in a Phase III study in patients with MS, and olebrutinib is being tested in a Phase II study. BIIB091 is being tested in a Phase I study for its efficacy in treating MS. It was.

[0014] Evobrutinib and trebrutinib are classified as covalent irreversible BTK inhibitors. The BTKi binding mechanism of fenebrutinib has been described as non-covalent and reversible. do.

[0015] In mid-stage trials, trebrutinib reduced the incidence of MS lesions and reduced headaches and Flu-like symptoms were the most common adverse event (Dolgin, E. BTK bl ockers make headway in multiple sclerosi s.Nat.Biotechnol.39,3-5(2021)).

[0016] Evobrutinib has been shown to be effective in animal models and in clinical trials for RA and SLE, as well as in Phase II trials for RRMS. It has been tested in phase 2 safety and efficacy studies.

[0017] In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, evobrutinib The drug was effective at a dose of 3 mg / kg, but the effect was further improved at a dose of 10 mg / kg. This supported the idea of ​​complete BTK inhibition at 3mg / kg (Torke, S. et al.,Inhibition of Bruton's tyrosine k inase interferes with pathogenic B-cell development in inflammatory CNS demyelin ating disease,Acta Neuropathol.140,535-5 48(2020)).

[0018] Epilepsy as monotherapy for RRMS (relapsing-remitting multiple sclerosis) and active secondary progressive MS In a Phase II trial of evobrutinib, three doses of evobrutinib (25 mg once daily) were , 75 mg once daily or 75 mg twice daily) versus placebo or dimethyl fumarate (DMF) Patients receiving the higher dose of evobrutinib, 75 mg once or twice daily, were randomized to receive Patients with relapsing MS who received the drug experienced fewer side effects compared with patients who received placebo or dimethyl fumarate. Patients with nasopharyngeal inflammation, however, tended to develop smaller brain lesions and experience fewer recurrences. Separately, the higher dose of evobrutinib, 75 mg once daily and twice daily, is Aminotransferase (ALT), aspartate aminotransferase (A ST) and lipase, thus raising safety concerns (M ontalban X.et al.,2019,N Engl J Med;380( 25):2406-17).

[0019] Currently, it is being studied in participants with relapsing multiple sclerosis (RMS), taking it orally twice daily. Evobrutinib was compared with teriflunomide administered orally once daily in a randomized controlled trial to assess its efficacy and safety. Phase III trials evaluating this are ongoing.

[0020] Considering the potential adverse events and incompletely established efficacy of these BTK inhibitors, Considering these, improved BTK inhibitors that may be effective and safe, especially in the long-term treatment of MS, are needed. A harmful agent is required. Summary of the Invention

[0021] The problem underlying the present invention is to provide an improved treatment for MS patients, especially for long-term treatment. In particular, the object of the present invention is to provide an advantageous MS therapy, preferably a very The objective of the present invention is to provide an effective MS therapy for

[0022] Another object is to provide a method for the treatment of B cell-depleting diseases, particularly those involving CD19 and / or CD20, that is as effective as B cell depleting therapy. The goal is to provide an MS therapy that is as effective as depletion therapy.

[0023] Another objective is to develop a method for the treatment of B-cell hyperplasia without undesirably affecting serum levels of immunoglobulins. The objective of the present invention is to provide an MS therapy that is as effective as cell-depleting therapies.

[0024] A further objective is to be effective in reducing the annual relapse rate, particularly in reducing the annual relapse rate. The objective of the present invention is to provide an MS therapy that is as effective as B cell depletion therapy in treating MS.

[0025] A still further object is to provide an MS treatment that can slow the progression of disability. And so.

[0026] Another objective is to provide a novel therapeutic option that is more effective than other approved oral disease-modifying and B-cell depleting therapies, particularly in patients with C In particular, an improved safety and tolerability profile compared to D19 / CD20 depletion therapy The objective of the present invention is to provide an improved MS therapy that demonstrates

[0027] The problem was unexpectedly solved by administration of LOU064 or a pharma- ceutically acceptable salt thereof. It was.

[0028] LOU064 (=N-(3-(6-amino-5-(2-(N-methylacrylamide) Ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclo Propyl-2-fluorobenzamide (INN: remibrutinib) is an anti-Bruton's type tyrosine kinase inhibitor. As a drug candidate for selective inhibition of tyrosine kinase, WO 2015 / 079417A The compound is disclosed in the brochure of No. 1 of the journal Nature. It is a potent and highly selective irreversible covalent bond. LOU064 is a potent BTK inhibitor. Due to its binding to the inactive conformation of BTK, Exhibiting sophisticated kinase selectivity, thus reducing off-target binding of kinases Due to covalent inhibition, the compounds do not require high systemic compound exposure for extended periods of time. It shows a strong and sustained pharmacodynamic effect on ry of LOU064(Remibrutinib),a Potent and Highly Selective Covalent Inhibitor of B ruton'S Tyrosine Kinase,J Med Chem.2020 May 28;63(10):5102-5118).

[0029] Chronic idiopathic urticaria (CSU) (International Publication No. 2020 / 234782A1) ) and Sjögren's syndrome (SjS) (International Publication No. Pamphlet 2020 / 23478 LOU064, which has previously been proposed for use in the treatment of is currently being tested in a Phase II clinical study in CSU and SjS.

[0030] In the WO 2020 / 234782A1 brochure, the maximum effective Doses of 10 mg, 25 mg, and 100 mg are generally administered bid to achieve efficacy. The proposal was made.

[0031] H 1 Patients with at least moderately active CSU that is not adequately controlled by antihistamines The second study will evaluate the efficacy and safety of LOU064 over a 12-week period in patients In a Phase B randomized, double-blind, placebo-controlled study, LOU064 10 mg qd (once daily), 35 mg qd, 100 mg qd, 10 mg bid( twice daily), 25 mg bid, 100 mg bid, or placebo (1: Patients received the 25 mg bid regimen. It has been found to be particularly effective compared to other doses.

[0032] Therefore, for the subsequent Phase III clinical study of CSU, 25 mg bid A dose of 100 mg / kg / day was selected.

[0033] BTK occupancy in blood and / or tissues was assessed for clinical studies such as the CSU and SjS studies. It has been reported that this is a suitable biomarker for dose selection (International Publication No. 202 Pamphlet No. 0 / 234782 and Pamphlet No. WO 2020 / 234781 ).

[0034] Furthermore, BTK occupancy and duration of BTK occupancy differed in the blood and various tissues of female rats. It has been reported that this is the case (International Publication No. 2020 / 234781).

[0035] Preclinical studies evaluating BTK occupancy of LOU064 have already demonstrated A single oral dose of 64 resulted in full BTK occupancy in the blood and spleen of female rats. The duration of BTK occupancy was determined in rats after a single oral dose of LOU064. The K half-life was approximately 87 hours in the blood, but only approximately 5 hours in the spleen. Without wishing to be bound by any theory, it is believed that BTK occupancy in the blood is sustained for a longer period. This suggests that BTK-expressing cells in peripheral blood are more quiescent than those in tissues such as the spleen, lymph nodes, and lungs. It has been hypothesized that this may reflect its relative metabolic inactivity.

[0036] BTK occupancy in different tissues may be important in determining efficacy and optimal dosage selection for different indications. However, all tissues associated with the symptoms of multiple sclerosis, and therefore M The overall picture of which tissues need to be invaded to treat S. Consent not obtained. As reported in rats, BTK occupancy and BTK occupancy half-life differs in blood and in various tissues.

[0037] The BTK half-life depends on the turnover rate (the ability of cells to reproduce). Such turnover rates vary in different tissues and are species specific. The efficacy and safety of the compound will depend on its PK / PD properties, which are also species dependent.

[0038] Blood BTK occupancy may not perfectly correlate with MS symptoms. was discovered.

[0039] BTK occupancy in other tissues, such as the spleen, lymph nodes, and lungs, was significantly higher than that in the blood. In addition, BTK occupancy in the brain may also correlate with efficacy in treating MS symptoms. This may be another factor related to the effectiveness of the treatment.

[0040] Brain occupancy of BTK depends on several factors. For example, one factor is the blood-brain barrier permeability of a compound, which is related to the P-glycoprotein Its affinity for the transporter controls the extent of efflux pumping out of the brain.

[0041] Because we could not detect BTK in the brains of naive mice, especially in the corpus callosum, we considered another factor. The reason for this is the uncertainty regarding the expression of BTK in the brain (Figure 19).

[0042] Therefore, to determine the effective dose of BTK inhibitors for the treatment of MS, There's Bell's unpredictability.

[0043] To evaluate the in vivo efficacy of LOU064, mouse experimental autoimmune encephalitis (EEE) was administered. Compounds were tested in the AE model. At this dose, complete BTK occupancy was observed in the spleen and lymph nodes 1 hour after administration ( 4 and 5). However, this dose of 3 mg / kg bid LOU064 Although full BTK occupancy in the spleen and lymph nodes was achieved at this dose, However, it only produced a rather weak reduction in neurological symptoms and EAE-induced weight loss (Figure 1). .

[0044] Therefore, the BTK occlusion complex was not detected in the brain homogenates prepared for compound exposure analysis. In contrast to what was observed in the spleen and lymph nodes, The 1 g dose surprisingly resulted in minimal BTK occupancy in brain homogenates at the 1 hour time point. However, even more surprisingly, at 30 mg / kg b. The dose group receiving id LOU064 showed the greatest BTK occupancy.

[0045] Complete BTK occupancy in the brain required a higher dose (30 mg / kg bid). Taking into account this, according to the present invention, the LOU0 at a dose of 30 mg / kg bid 64 significantly reduced neurological symptoms and EAE-induced weight loss in mice. It was found.

[0046] In addition, spleen tissue was determined 1, 5, and 8 hours after bid oral administration of LOU064. The BTK occupancy in the 30 mg / kg mice (Fig. 4) also showed a more sustained occupancy after administration of 30 mg / kg. .

[0047] Without being bound by theory, we conclude that BTK occupancy in the brain may be more relevant for the treatment of MS. It was argued that BTK could not be detected in the brains of naive mice, especially in the corpus callosum. , which was completely unexpected (Figure 19).

[0048] Animal-human transformation model (Journal of basic and clinical ical pharmacy, 7(2), 27-31) The calculated human equivalent dose (HED) for .id is approximately 17 for a 70 kg person. 0 mg (Nair, A.B., & Jacob, S. (2016).

[0049] Finally, predictive models of BTK occupancy in humans suggest that bid dosing is more effective at reducing BTK occupancy in humans. It was shown to be more effective than the same dose of QD to achieve high BTK occupancy. Therefore, LOU064 at 100 mg bid was administered for the clinical study. A dose of 100 mg / kg was selected.

[0050] Particularly surprising, LOU064 was administered orally at a dose of 100 mg twice daily. It has already demonstrated excellent efficacy and safety in the treatment of multiple sclerosis.

[0051] The subject of the present invention is therefore LOU064 or and its pharma- ceutically acceptable salts.

[0052] In general, the present invention relates to the treatment of multiple sclerosis. In a preferred embodiment of the present invention, OU064 is intended to be used to treat relapsing-remitting multiple sclerosis (RRMS), secondary Progressive multiple sclerosis (SPMS), especially active SPMS, and clinically isolated syndrome ( Recurrent types including clinically isolated syndrome (CIS) It is administered for the treatment of relapsing multiple sclerosis (RMS).

[0053] In particular, the present invention relates to the treatment of relapsing-remitting multiple sclerosis (RRMS). The invention relates to the treatment of secondary progressive MS (SPMS), in particular active SPMS. Specifically, the present invention relates to the treatment of clinically isolated syndrome (CIS).

[0054] In one embodiment, LOU064 is administered at a dose of about 10 mg to about 500 mg twice daily, or A dose of about 25 mg to about 400 mg twice a day, or a dose of about 50 mg to about 300 mg twice a day or a dose of about 50 mg to about 250 mg twice a day, or a dose of about 50 mg to about 150 mg twice a day It is administered orally in a dose of 1 g.

[0055] Preferably, LOU064 is administered at a dose of about 50 mg to about 150 mg twice daily, more preferably It is usually administered orally at a dose of about 100 mg twice daily.

[0056] In another embodiment, LOU064 is administered at a dose of about 100 mg to about 300 mg twice daily, more preferably More preferably, it is administered orally at a dosage of about 250 mg twice daily.

[0057] In a suitable pharmaceutical formulation, LOU064 may be present in any pharma- ceutically acceptable form. LOU064 is present in pharmaceutical formulations as nano- or micro-sized particles. It may be preferable to

[0058] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, the average particle size is 100 Preferably, the average particle size of LOU064 is less than 500 nm, more preferably less than 500 nm. It may preferably be less than 250 nm.

[0059] In a preferred embodiment, the average particle size of LOU064 is between about 50 nm and about 1000 nm. or between about 50 nm and about 750 nm, or between about 60 nm and about 500 nm, or between about 70 It may be between about 100 nm and about 170 nm. For example, the average particle size of LOU064 is between about 100 nm and about 350 nm, or about 110 nm. between about 120 nm and about 200 nm, or between about 120 nm and about 180 nm, or between about 120 nm and about 160 nm, and preferably, the average particle size of LOU064 is about 150 nm to about 200 nm. It could be.

[0060] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, oral administration is preferred. Or, a dose of about 50 mg to about 150 mg twice a day, more preferably about 100 mg twice a day. The dosage is g.

[0061] When LOU064 is present in the pharmaceutical formulation in the form of micro-sized particles, the average particle size is 1 The thickness of the LOU064 nanoparticles may be 1.0 to 5 μm, or preferably 1.0 to 1.5 μm. The average particle size may be from 1.1 to 1.3 μm.

[0062] When LOU064 is present in the pharmaceutical formulation in the form of micro-sized particles, oral administration Preferably, the dose is about 100 mg to about 300 mg twice a day, for example about 100 mg twice a day. The dosage is:

[0063] In a preferred embodiment, the polydispersity index (PI) is between 0.01 and 0.5, more preferably The particle size distribution is preferably between 0.1 and 0.2, and more preferably between 0.12 and 0.14. will be done.

[0064] The average particle size above is intensity weighted. The average particle size was determined using dynamic light scattering. Preferably, the average particle size is determined by photon correlation spectroscopy (PCS). In particular, a Malvern Panalytical L Zetasizer Nano ZS, version 7.13, from td., UK can be used.

[0065] Preferably, the measurements are performed using a 0.1 mM NaCl solution in purified water (1:10). The method is carried out as a dispersion method with a decay exponent of 2 to 9, in particular 5. The measurement is preferably carried out at 25° C. Further preferred settings for the measurement system are as follows: Cell: Disposable sizing cuvette Count rate (kcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65.

[0066] In one embodiment of the present invention, the LOU064 composition is a pharmaceutical composition suitable for oral administration to humans. Compositions for oral administration are typically formulated in the form of capsules. It is a cell or tablet.

[0067] In one embodiment, the formulation of LOU064 is According to the formulations disclosed in U.S. Patent Application No. 63 / 141558 or its family members. It can be formulated as such.

[0068] According to the present invention, a pharmaceutical composition suitable for oral administration comprises LOU064 and a binding agent.

[0069] Suitable binders include polyvinylpyrrolidone-vinyl acetate copolymers, ... Don, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Hyprome Roth, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose , carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene Ethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene polyethylene glycol copolymer, polyethylene-propylene glycol copolymer, or The binder may be a mixture of polyvinylpyrrolidone-vinyl acetate copolymer. It is a polymer.

[0070] The weight ratio of LOU064 and binder is about 3:1 to about 1:3; for example, about 3:1, about 2: 1, about 1:1, and preferably, the weight ratio of LOU064 and binder is about 2 :1 or about 1:1.

[0071] Preferably, the pharmaceutical composition suitable for oral administration comprises LOU064, a binder and a surfactant. include.

[0072] Suitable surfactants include sodium lauryl sulfate, potassium lauryl sulfate, lauryl sulfate, Ammonium Lauryl Ether Sulfate, Sodium Lauryl Ether Sulfate, Polysorbate, Perfluorobutene The preferred sulfonates include butyl sulfonate, dioctyl sulfosuccinate, or mixtures thereof. In the present invention, the surfactant is sodium lauryl sulfate.

[0073] The weight ratio of LOU064, binder and surfactant is about 2:1:0.5, or about 2:1: 0.1, or about 2:1:0.08, or about 2:1:0.05, or about 2:1:0.04, or about 2:1:0.03, or about 2:1:0.02. The weight ratio of binder and surfactant is about 2:1:0.08 or about 1:1:0.05.

[0074] In a particularly preferred embodiment, a pharmaceutical composition suitable for oral administration comprises LOU064, a binding agent and and a surfactant, wherein the binder is polyvinylpyrrolidone-vinyl acetate copolymer ( Copovidone) and the surfactant is sodium lauryl sulfate (SLS), LOU0 LOU064 is a preferred formulation with a weight ratio of copovidone and SLS of about 2:1:0.08. Preferably, the nanoparticles have an average particle size between about 100 nm and about 200 nm as measured by PCS. It is further particularly preferred that the compound is present in the pharmaceutical composition in the form of mono-sized particles.

[0075] If a dose of LOU064 is missed, it should be administered as soon as possible, preferably without waiting until the next scheduled dose. Subsequent doses should be given at the recommended intervals.

[0076] In a Phase I clinical study, single doses of up to 600 mg and additional 100 mg bi Short-term safety of LOU064 was demonstrated for up to 18 days in patients with .d. No data were available regarding completeness.

[0077] Observed with the covalent irreversible BTK inhibitors evobrutinib and trebrutinib Dose-limiting side effects (evobrutinib was administered at 75 mg bid in Phase II clinical studies) Already at doses of 100 mg / kg, patients showed dose-limiting elevations in liver enzymes, and trebrutinib showed dose-limiting diarrhea. (Becker A. et al., 2019, Clin Transl Sci; 13,325-336;Montalban X.et al.,2019,N Eng l J Med;380(25):2406-17,Smith PFet al. ,2019,ACTRIMS Forum,Feb 28,2019,P072) A longer-term, higher dose of LOU064 at 100 mg bid was then It is quite surprising that LOU064 does not induce such adverse effects, especially in the long term. In particular, LOU064 is suitable for long-term treatment at a dose of 100 mg / kg for a long period of time. Does not induce dose-limiting liver enzyme elevations or other off-target effects at bid doses .

[0078] In particular, LOU064 surprisingly showed longer-lasting effects than other DMTs, especially other BTK inhibitors. Not only does it prevent unwanted side effects while providing a long-term therapeutic benefit, but it also has a shorter therapeutic benefit than other DMTs, especially other BTK inhibitors. It has been found that the active ingredient retains its activity, i.e., maintains its effectiveness, for a longer period of time than the active ingredient.

[0079] Even more surprisingly, LOU064 showed longer-lasting effects than other DMTs, especially other BTK inhibitors. It was found that the drug delayed the worsening of symptoms for a short period of time.

[0080] Thus, in a preferred embodiment of the present invention, LOU06 is administered orally for use in the treatment of MS. 4 or a pharma- ceutically acceptable salt thereof is used in chronic therapy. , indicating that LOU064 or a pharma- ceutically acceptable salt thereof is to be used for a long period of time. For example, LOU064 or a pharma- ceutical acceptable salt thereof may be administered for 2 years, 3 years, 4 years, 5 years, 1 year, LOU064 or a pharma- ceutical acceptable salt thereof can be used for more than 5 It may be used for up to a year, 10 years, 15 years, 20 years, or for life.

[0081] Treatment of multiple sclerosis can take decades, so there is a high risk of adverse effects, treatment failure, and breakthroughs. cross-sectional disease, disease progression, comorbidities, life cycle events (e.g. pregnancy and lactation), and / or the need to modify the treatment plan to accommodate changing circumstances, such as changing patient preferences. Sexuality often occurs.

[0082] Switching drugs or completely discontinuing immunomodulatory agents may leave patients vulnerable to relapse or disease progression. In some cases, severe clinical and MRI MS disease may develop after treatment withdrawal. This disease activity is disproportionate to the pattern observed before treatment began. If this is not the case, the patient is said to have experienced rebound.

[0083] According to the present invention, LOU064 offers a potent and effective therapeutic strategy to prevent relapse. LOU064 also provides a potent and efficacious treatment for other DMT-induced breakthrough diseases. Furthermore, LOU064 has been shown to reduce rebound after cessation of another DMT. This provides a powerful and effective treatment strategy to prevent

[0084] Thus, in one embodiment, LOU064 is administered in combination with a disease-modifying therapy other than LOU064. In other words, it is used in patients who have been previously treated with a disease-modifying agent other than LOU064. Patients previously treated with disease-modifying therapy will be switched from their previous disease-modifying therapy to LOU064.

[0085] In one embodiment, the prior disease modifying therapy drug other than LOU064 is a B cell and / or T-cell inhibitors, teriflunomide, mitoxantrone, dimethyl fumarate, cladribine, Fingolimod, siponimod, ponesimod, glatiramer acetate and beta interferon is selected from the following:

[0086] In a preferred embodiment, LOU064 is administered to patients with adverse events, such as severe infusion-related reactions or recurrent infections. It is administered to patients who have discontinued a previous DMT, e.g., anti-CD20 therapy, for this purpose.

[0087] In a preferred embodiment, the patient is treated with one or more of the following disease modifying therapies if previous disease modifying therapies have lacked efficacy: Patients will be switched from their previous disease-modifying therapy to LOU064. Lack of efficacy may be due to, for example, Patients receiving decorative marker therapy (DMT) show signs of disease activity, such as recurrence or lesions. Lack of efficacy is due to failure to stop or adequately slow disease progression. In other words, the present invention can be defined as a non-response to previous DMT. The present application relates to the use of LOU064 to treat

[0088] In another preferred embodiment, the patient is treated with a disease modifying therapy in which the patient has poor tolerance to the previous disease modifying therapy. Patients may be switched to LOU064 from their previous disease-modifying therapy if Lack of tolerance may include headache, dizziness, nausea, infections (e.g., shingles), macular edema, infusion-related reactions, or In a preferred embodiment of the present invention, LOU0 is associated with the presence of adverse events such as recurrent infections. Prior disease-modifying therapy other than LOU064 will be discontinued prior to initiation of LOU064 administration.

[0089] In general, LOU064 and another disease-modifying therapy may be pursued simultaneously, but LOU064 4 Treatment is preferably a monotherapy, i.e. LOU064 is preferably administered It is the only disease-modifying drug that can be used to treat

[0090] Thus, in one embodiment, LOU064 is administered to patients with multiple sclerosis. This treatment is a monotherapy.

[0091] LOU064 is predicted to be a sensitive CYP3A substrate and a potent CYP3A4 inhibitor. It can be excluded that coadministration with drugs may increase the oral drug exposure several-fold. Similarly, strong inducers of CYP3A4 may significantly reduce exposure and therefore efficacy. These properties of LOU064 may be related to not only MS but also BTK-induced It is relevant to all situations.

[0092] Coadministration of strong CYP3A4 inhibitors and / or inducers may adversely affect the efficacy and safety of LOU064. CYP3A4 inhibitors may cause substantial changes in drug exposure and should be avoided. Antimicrobials include boceprevir, clarithromycin, cobicistat, conivaptan, and danopeptide. Levir / ritonavir, darunavir / ritonavir, elvitegravir / ritonavir, grey pudding juice, idelalisib, indinavir, indinavir / ritonavir, itra Conazole, ketoconazole, LCL161, lopinavir / ritonavir, mibefradil, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Saquinavir, Saquinavir / ritonavir, telaprevir, telithromycin, tipranavir / ritonavir, tolosair Strong CYP3 inhibitors such as endomycin, Viekira Pak, and / or voriconazole Includes A4 inhibitors.

[0093] Thus, in another preferred embodiment, LOU064 is a potent inhibitor of CYP3A4. The drug will not be administered in combination with anti-inflammatory and / or inducing agents.

[0094] Furthermore, LOU064 significantly increased the efficacy and safety of ethinyl esterase inhibitors without significantly affecting their exposure and efficacy. Can be administered simultaneously with oral contraceptives such as luestradiol or levonorgestrel It has been found that LOU064 is an oral contraceptive. are administered simultaneously.

[0095] In a preferred embodiment, no premedication is administered prior to the first dose of LOU064.

[0096] As a covalent, irreversible BTK inhibitor, LOU064 inhibits de novo protein synthesis It acts by irreversible inhibition of BTK, which is counterbalanced by β-lactamase. We do not wish to be bound by this, but reconstitution of the B cell pool after B cell depletion takes several months. Possibly, but recovery of B cell function after BTK inhibition occurs soon after cessation, particularly within a few days. Therefore, if necessary, this therapy should be stopped promptly. This allows clinicians and patients to more easily and quickly respond when unexpected situations arise. You will be able to react.

[0097] Thus, in one embodiment, the patient is planning to become pregnant within the next 12 months. In this case, LOU064 is advantageously selected.

[0098] In another embodiment, if the patient intends to receive chemotherapy within the next 12 months, LOU064 is advantageously selected.

[0099] Especially in light of the 2020 COVID-19 pandemic, B cells are depleted. Patients with HIV are at higher risk of infection. In addition, they lack a fully functional adaptive immune response. may lead to a more severe course.

[0100] However, LOU064 does not result in depletion of the B cell pool, so cessation of treatment This allows for rapid restoration of full B-cell function, allowing patients and treating physicians to requirements for vaccination, particularly with live and attenuated vaccines; This enables quick response.

[0101] According to the present invention, LOU064 is administered during infection, e.g., during COVID-19 infection. Thus, administration of LOU064 may be useful in preventing and treating COVID-19 infections during infection. It can be continued in

[0102] Alternatively, administration of LOU064 may be used in patients with active infection, such as COVID-19 patients. The treatment is delayed until the infection has resolved in the individual.

[0103] Thus, one embodiment of the present invention provides LOU06 for use in the treatment of multiple sclerosis. Regarding 4, where patients with acute or previous COVID-19 infection are being treated can be.

[0104] In a preferred embodiment, LOU064 treatment is continued during COVID-19 infection. .

[0105] In a further embodiment, treatment with LOU064 is interrupted during COVID-19 infection and It continues after the stain is overcome.

[0106] Yet further embodiments of the present invention relate to the use of BTK-mediated conditions, particularly multiple sclerosis. and LOU064 for use in a patient receiving a vaccine during LOU064 therapy. Alternatively, patients may be vaccinated with a non-live vaccine during LOU064 therapy. Can be seeded.

[0107] In one embodiment, the patient is treated during LOU064 therapy (e.g., after the initiation of LOU064 therapy). 15 days after vaccination), quadrivalent influenza vaccine, PPV-23 vaccine or KLH neoa In one aspect of this embodiment, the patient is vaccinated with a tetravalent influenza vaccine. Patients receiving the Enza vaccine had a mean score of 0.01 or 0.02 at 28 days after vaccination compared to baseline. A more than four-fold increase in anti-hemmaglutinin antibody titer In another aspect of this embodiment, the PPV-23 vaccine achieves a response defined as Patients receiving the vaccine had a doubling of IgG titers 28 days after vaccination compared to baseline In yet another embodiment, the KLH neoantigen vaccine is administered to achieve an increase of 100%. Patients with KLH infection were randomly assigned to receive the vaccine, as determined by anti-KLH IgG and IgM titers 28 days after vaccination. The antibody achieves a T cell dependent antibody response.

[0108] Another embodiment of the present invention provides a method for the treatment of BTK-mediated conditions, particularly multiple sclerosis. Regarding LOU064 for the treatment of HIV-1 infection, where LOU064 treatment is discontinued for vaccination, In particular, LOU064 treatment is preferably administered 5 to 10 days (e.g., 7 or 8 days) prior to vaccination. The vaccination should be stopped 6 weeks or earlier, preferably 5 to 20 days after vaccination. Preferably, the treatment is continued for 5 to 10 days, or most preferably for 10 to 15 days. In certain embodiments of the present invention, the patient is treated with LOU064 therapy after cessation of LOU064 therapy (e.g., 5 to 10 days or 7 or 8 days after discontinuation) quadrivalent influenza vaccine, PPV The patients will be vaccinated with the -23 vaccine or the KLH neoantigen vaccine. In one embodiment, patients receiving the quadrivalent influenza vaccine have a mean mean of 1.1 months to 1.2 months compared to baseline. defined as a greater than four-fold increase in anti-hemagglutinin antibody titers 28 days after vaccination compared with placebo. In another aspect of this embodiment, the subject is a patient who has received the PPV-23 vaccine. Patients demonstrated a greater than two-fold increase in IgG titers 28 days after vaccination compared to baseline In yet another embodiment, a patient receiving a KLH neoantigen vaccine , T cells measured by anti-KLH IgG and IgM titers 28 days after vaccination The LOU064 treatment was then continued from day 29 after vaccination. To be continued.

[0109] In an alternative embodiment, vaccination is with a live and / or attenuated vaccine. In a preferred embodiment, LOU064 is administered in a manner that is consistent with weight, sex, age, race, or It can be administered regardless of baseline B cell count. For example, A woman of 20 kg should preferably receive the same dose as a 50 year old man weighing 90 kg. The following factors may have clinical significance for the pharmacokinetics of LOU064: sex, age, race, or baseline B-cell count. Does not have any flavorful effect.

[0110] According to the present invention, LOU064 treatment is similarly effective in people of all races or ethnicities. do.

[0111] Thus, the present invention further relates to LOU064 for use in the treatment of multiple sclerosis. where the treatment is an ethnically independent treatment.

[0112] In one embodiment of the present invention, LOU064 or a pharma- ceutically acceptable derivative thereof is used for the treatment of MS. Patients receiving ribavirin-containing salts are selected according to the following criteria: - Patients will have an EDSS score of 0 to 5.5 prior to the first dose of LOU064. - Patients must have had at least one relapse within the past year prior to the first dose of LOU064, or have had two relapses in the past two years, and - Patients must have had a positive Gd-enhanced MR within the past year / 6 months prior to their first dose of LOU064 Had an I scan.

[0113] In a preferred embodiment of the invention, LOU064 is administered after relapse.

[0114] In another preferred embodiment of the invention, LOU064 is administered in a dose-dependent manner, prior to the first administration of LOU064: It is administered after detection of at least one Gd+ lesion in the previous 12 months.

[0115] In yet another preferred embodiment of the invention, LOU064 is administered to treat new T2 lesions or enlargement. It is administered after detection of T2 lesions associated with

[0116] In another embodiment of the invention, LOU064 is a therapeutic option that offers a less favorable risk / benefit ratio. In patients for whom S1P modulator therapy is not an option due to their Such patients may be selected for use in a clinical setting, for example, to assess the cardiac or cardiac rhythm, respiratory function, susceptible to or suffering from one or more diseases or disorders affecting the immune system, eyes, or liver function In particular, these patients may experience adverse events, such as temporary slowing of heart rate and cardiac conduction. Patients who may be more susceptible to the event are included.

[0117] In the present invention, unexpectedly, administration of LOU064 has at least one of the following effects: It has been found to be beneficial: - Compared to untreated patients and / or to interferon, teriflunomide, glucagon acetate Latiramer and dimethyl fumarate, preferably interferon, teriflunomide and More preferably, it is selected from dimethyl fumarate, teriflunomide or interferon. Reduction in the mean total number of gadolinium-enhancing lesions compared with patients receiving alternative disease-modifying treatments Few, - Compared to untreated patients and / or to interferon, teriflunomide, glucagon acetate Latiramer and dimethyl fumarate, preferably interferon, teriflunomide and Dimethyl fumarate, more preferably teriflunomide or interferon Annualized relapse rate compared with patients receiving another disease-modifying treatment selected from the following: Decline in - Interferon, teriflunomide, glatiramer acetate and dimethyl fumarate, preferred Preferably, interferon, teriflunomide and dimethyl fumarate, more preferably Patients receiving another disease-modifying therapy selected from teriflunomide or interferon Compared with 3-month confirmed disability progression, Prolonged time to achieve AB progression.

[0118] In this regard, a further subject of the invention is a compound for use in the treatment of relapsing multiple sclerosis. LOU064, where LOU064 is within a maximum of 60 months or within a maximum of 30 months. Within 24 months, or up to 24 months, preferably within 12 to 24 months, compared with untreated patients , and / or interferon, teriflunomide, glatiramer acetate, dimethyl fumarate , preferably interferon, teriflunomide and dimethyl fumarate, more preferably Patients receiving another disease-modifying therapy selected from teriflunomide or interferon Reduces the mean total number of gadolinium-enhancing lesions compared with

[0119] Yet a further subject of the present invention is a compound comprising LOU0 for use in the treatment of relapsing multiple sclerosis. 64, where LOU064 is up to 60 months, or up to 30 months, or within a maximum of 24 months, preferably within 12 to 24 months, compared to untreated patients, and / or or interferon, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably or interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide. Patients receiving another disease-modifying therapy selected from liflunomide or interferon In comparison, this results in a reduction in the annualized recurrence rate.

[0120] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, interferon, teriflunomide, and glucagon acetate should be administered. Latiramer and dimethyl fumarate, preferably interferon, teriflunomide and More preferably, it is selected from dimethyl fumarate, teriflunomide or interferon. time to achieve 3-month sustained disability progression compared with patients receiving another disease-modifying treatment This results in a longer time in

[0121] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with untreated patients and / or feron, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide compared with patients receiving another disease-modifying therapy selected from the group consisting of cyclophosphamide or interferon One or more patient-reported outcomes ) (PRO) (i.e., MSIS-29, PHQ-9, GAD-7, FSIQ-RMS and BPI-SF) .

[0122] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, one or more patients Patient-reported outcomes (PROs) (i.e., MSIS-29, PHQ-9, GAD-7, F The reduction in MS symptoms measured by scores on the SIQ-RMS and BPI-SF In one aspect of this embodiment, the improvement in MS symptoms is up to 60 months, or up to 30 months, or up to 2 Within 4 months, preferably within 12 to 24 months, MSIS-2 This is achieved by a reduction of at least 6 points (preferably at least 8 points) on a 9-point scale. In another aspect of this embodiment, improvement in MS symptoms is associated with LOU064 (100 mg bid). Within a maximum of 60 months, or within a maximum of 30 months, or within a maximum of 24 months, preferably after treatment with At least one improvement in PHQ9 score compared to baseline, preferably within 12-24 months Achieved by a reduction of 2 points (preferably at least 3 points, more preferably at least 5 points) In yet another aspect of this embodiment, the improvement of MS symptoms is up to 60 months, or up to 30 months, or up to 2 Within 4 months, preferably within 12 to 24 months, the GAD-7 score will be increased compared to baseline. This is achieved by a reduction of at least two points (preferably at least three points) of the core. In yet another aspect of the embodiment, improvement in MS symptoms is achieved by administering LOU064 (100 mg bid). ) for up to 60 months, or up to 30 months, or up to 24 months after treatment with A decrease in BPI-SF score compared to baseline, preferably within 12 to 24 months This is accomplished by a reduction of at least one point (preferably at least two points).

[0123] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with untreated patients and / or feron, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide compared with patients receiving another disease-modifying therapy selected from the group consisting of cyclophosphamide or interferon MS symptoms as measured by increased HUI-III patient-reported outcome (PRO) scores This results in improvement of the condition.

[0124] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with baseline, Results in improvement of MS symptoms as measured by increased patient-reported outcome (PRO) scores In one aspect of this embodiment, improvement in MS symptoms is observed with LOU064 (100 mg bid). ) for up to 60 months, or up to 30 months, or up to 24 months after treatment with Preferably within 12 to 24 months, at least 0.02 points in the HUI score (preferably This is achieved by an increase of at least 0.03 points.

[0125] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with untreated patients and / or feron, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide compared with patients receiving another disease-modifying therapy selected from the group consisting of cyclophosphamide or interferon Results in improvement of MS symptoms as measured by a reduction in SDMT score.

[0126] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. A reduction in SDMT compared to baseline within months, preferably within 12 to 24 months In one aspect of this embodiment, improvement in MS symptoms is measured by Improvement was observed within a maximum of 60 months or after treatment with LOU064 (100 mg bid). SDMT will be performed within 30 months or within a maximum of 24 months, preferably within 12 to 24 months. This is accomplished by a reduction of at least 3 points (preferably at least 5 points) of the core.

[0127] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with untreated patients and / or feron, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide compared with patients receiving another disease-modifying therapy selected from the group consisting of cyclophosphamide or interferon This results in an increase in walking speed as measured by the T25FW.

[0128] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, the T25FW will Baseline T25FW results were consistent with LOU06 Defined as the last assessment prior to the first dose of 4.

[0129] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Within months, preferably within 12 to 24 months, compared with untreated patients and / or feron, teriflunomide, glatiramer acetate and dimethyl fumarate, preferably interferon, teriflunomide and dimethyl fumarate, more preferably teriflunomide compared with patients receiving another disease-modifying therapy selected from the group consisting of cyclophosphamide or interferon This results in increased speed at which patients can perform the 9HPT test.

[0130] Another subject of the present invention is LOU064 for use in the treatment of relapsing multiple sclerosis. , where LOU064 is up to 60 months, up to 30 months, or up to 24 months. Patients will have a 9HPT test score within months, preferably within 12-24 months, compared to baseline. Baseline 9HPT results are the first It is defined as the last assessment prior to the first dose.

[0131] The present invention further unexpectedly demonstrates that administration of LOU064 by week 12 or 24 of treatment This results in the activation of alanine aminotransferase (ALT) and aspartate aminotransferase (ASAT). Levels of AST, ferritinase, and lipase are advantageously at baseline levels at the start of treatment. It was found that the change did not exceed 10% compared to the previous test.

[0132] Unexpectedly, according to the present invention, administration of LOU064 advantageously reduces at least one of the following: It has been found to result in one: - 45-50%, preferably 55-60%, annualized relapse rate compared to teriflunomide A relative decline in the rate, - 60-75%, preferably 90-95%, of gadolinium compared with teriflunomide Relative reduction in the mean total number of Gd-enhancing lesions (Gd+T1), - 65-70% and preferably 80-85% of new / expanded relative reduction in T2 lesions, - Approximately 30% of the efficacy of teriflunomide, preferably 30-35%, lasting for 3 months Relative reduction in time to reach disability progression (3mCDP); - Six-month duration of approximately 30-35%, preferably 35-40%, compared with teriflunomide relative reduction in time to reach progressive disability (6mCDP); - 12-60 months, or 12-30 months, or 12-24 months, up to 6-7 / 10 Disease ability of 10 patients, preferably up to 8-9 / 10 patients ity) (NEDA-3), - A relative reduction in serum Nfl concentrations of at least 20% compared to teriflunomide.

[0133] Furthermore, unexpectedly, LOU064 treatment was comparable to CD20-depleting therapy in reducing annual relapse rates. Comparably effective, especially in reducing annual relapse rate compared with CD20-depleting therapy It was found that.

[0134] The present invention further relates to a method for the preparation of a medicament for use in the treatment of multiple sclerosis. Regarding 64, preferably, the drug is administered at a dose of about 50 mg to about 150 mg twice daily. It is administered orally.

[0135] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising For patients who need such treatment, the dosage is preferably about 50 mg to about 150 mg twice a day. The method includes administering LOU064 orally at a dose of

[0136] A further subject of the invention is a method for producing a medicament for use in the above-mentioned treatment. It is law. [Brief description of the drawings]

[0137] [Figure 1] Effect of prophylactic LOU064 (3 mg / kg po bid and 30 mg / kg po bid) on daily neurological deficits in human MOG EAE. LOU064 30 mg / kg po bid treatment significantly improved daily body weight change (A), suggesting a reduction in inflammation-induced cachexia. Consistent with the body weight data, LOU064 30 mg / kg po bid improved EAE scores (B). Group size, n=8-10 / treatment. Statistical significance was determined using Kruskal-Wallis test with Dunn's test (non-parametric ANOVA). [Diagram 2] Prophylactic LOU064 30 mg / kg (bid) significantly reduced disease incidence in human MOG EAE. LOU064 bid treatment reduced the frequency and rate of EAE onset. Group size was n=10 / treatment. Statistical significance was determined using the Kaplan-Meier non-parametric test. [Diagram 3] Prophylactic LOU064 dose-dependently reduced disease burden in human MOG EAE. LOU064 30 mg / kg bid treatment significantly reduced peak EAE scores (A) and cumulative disease burden (B). Group size is n=10 / treatment. Statistical significance was determined using Kruskal-Wallis test with Dunn's test (non-parametric ANOVA). [Figure 4]BTK occupancy in the spleen 1, 5 and 8 hours after the last dose of oral bid administration of LOU064. Occupancy levels of individual animals are shown. Group means are shown in the center bars and standard deviations are shown in the whisker error bars. Statistical significance (ANOVA followed by Dunnett's test) is indicated with **** where p<0.0001. One outlier in the vehicle group (112% BTK occupancy) was removed after Grubbs test. [Diagram 5] BTK occupancy in lymph nodes 1, 5, and 8 hours after the last dose of oral bid administration of LOU064. Occupancy levels of individual animals are shown. Group means are shown in the center bars and standard deviations are shown in the whisker error bars. Statistical significance (ANOVA followed by Dunnett's test) is indicated with **** where p<0.0001. [Figure 6] BTK occupancy in brain homogenates 1, 5, and 8 hours after the last dose of oral bid administration of LOU064. Occupancy levels of individual animals are shown. Group means are shown in the center bars and standard deviations are shown in the whisker error bars. Statistical significance (ANOVA followed by Dunnett's test) is indicated with ** where p<0.01. [Figure 7] Prophylactic LOU064 (bid) treatment in human MOG EAE only weakly modulates MOG-specific immunoglobulin responses. Oral LOU064 bid treatment significantly reduced MOG-specific IgM and IgG responses in serum; however, the effect was very weak (A, B). Subclass analysis revealed that IgG1 (C), IgG2a (D) and IgG2b (E) were reduced. No changes were detected in IgG2c (F). Group size was n=8-10 / treatment. Statistical significance (ANOVA with Dunnett's test) is indicated as *p<0.05, **p<0.01, * **p<0.001, ****p<0.0001. [Figure 8]Preventive LOU064 (bid) treatment in human MOG EAE ameliorates inflammation-induced cachexia. No neurological symptoms were observed in the pre-EAE stage of the model (A). Oral LOU064 bid treatment (30 mg / kg twice daily) improved weight gain in immunized mice, suggesting that inflammation-induced cachexia was reduced (B). Group size is n=5 / treatment. [Figure 9] Prophylactic LOU064 (bid) treatment in human MOG EAE inhibits (self-)antigen recall proliferation. Isolated splenocytes and draining lymph node cells were incubated with human MOG in vitro for 48 h. Antigen-specific proliferation was determined by [3H]-thymidine incorporation. Animals administered LOU064 in vivo demonstrated a dose-dependent decrease in MOG-specific proliferation (A, B), whereas polyclonal stimulation with anti-CD3 / CD28 was unchanged (C). Group size is n=5 / treatment. [Figure 10] Preventive LOU064 (bid) treatment in human MOG EAE reduces Th17 cells. Mice immunized with human MOG and administered LOU064 bid in vivo demonstrated no significant changes in the frequency of B cell populations (A, B). Total CD4+ T cell populations were unchanged (C); however, intracellular cytokine staining revealed a significant reduction in Th17 (IL-17+) cells (D). No changes were observed in Th1 or Tregs (E, F). Group size is n=5 / treatment. Statistical significance (ANOVA with Dunnett's test) is indicated as *p<0.05. [Figure 11] Prophylactic BTK inhibitor administered bid in rat MOG EAE shows no adverse responses. Daily bid administration of the BTK inhibitor (LOU064, ibrutinib) did not induce worsening of neurological symptoms (A) or weight change (B). Cyclosporine A (CsA) was associated with significant weight loss. Group size is n=4-5 / treatment. [Figure 12]Prophylactic BTK inhibitors administered bid in rat MOG EAE failed to inhibit (self-)antigen recall proliferation. Isolated draining lymph node cells were incubated with rat MOG in vitro for 48 h. Antigen-specific proliferation was determined by [3H]-thymidine incorporation. Animals were treated in vivo with BTK inhibitors (LOU064, ibrutinib or cyclosporine A (CsA) for 8 days. Group size was n=4-5 / treatment. [Figure 13] LOU064 reduced rat MOG EAE pathology. Daily body weight change (A) was significantly reduced by LOU064 30 mg / kg oral bid treatment, suggesting a reduction in inflammation-induced cachexia. Consistent with the body weight data, EAE scores were improved (B). Group size is n=10 / treatment. Statistical significance was determined using Kruskal-Wallis test with Dunn's test (non-parametric ANOVA). [Figure 14] LOU064 significantly reduced disease incidence in rat MOG EAE. LOU064 30 mg / kg bid treatment reduced the frequency and time to EAE onset (clinical score > 1). Group size was n = 10 / treatment. Statistical significance was determined using the Kaplan-Meier non-parametric test. [Figure 15] LOU064 reduced disease burden in rat MOG EAE. LOU064 30 mg / kg bid treatment significantly reduced peak EAE scores (A) and cumulative disease burden (B). Group size is n=10 / treatment. Statistical significance was determined using Kruskal-Wallis test with Dunn's test (non-parametric ANOVA). [Figure 16]Trough BTK occupancy in spleen, blood and brain. Trough BTK occupancy in spleen and blood indicates maximum target occupancy at peak. BTK occupancy assessed in brain homogenates showed intermediate levels in spleen (A), blood (B) and brain (C), suggesting that significant, but submaximal, brain BTK occupancy was achieved at peak. Statistical significance was determined by unpaired two-tailed t-test with Welch's correction. [Figure 17-1] LOU064 did not modulate MOG-specific immunoglobulin responses in rat MOG EAE. Oral LOU064 bid treatment did not affect MOG-specific IgM (A) and IgG (B) responses in serum compared to vehicle. Subclass analysis revealed that IgG1 (C), IgG2a (D) and IgG2b (E), IgG2c (F) and IgG3 (G) were not modulated. Group size was n=4-5 / treatment; p values ​​were determined between naïve and vehicle-treated mice. Statistical significance was analyzed by ANOVA followed by Dunnett's test. [Figure 17-2] (As stated above.) [Figure 18] NF-L concentrations in serum were slightly decreased by LOU064 treatment (FIG. 18A) and correlated with EAE clinical scores (FIG. 18B). Oral LOU064 bid treatment slightly decreased mean serum NF-L levels compared to the vehicle-treated group. NF-L levels in serum correlated with clinical scores observed at termination. UDL=upper limit of detection; LDL=lower limit of detection. Statistical differences were determined using simple linear regression tests. [Figure 19] In naive mice, BTK is expressed in lymph nodes but not in the brain. Histological examination of lymph nodes and brains from naive mice shows BTK expression in lymph nodes (A), particularly in B cell follicles (B), scattered in the paracortex. No BTK expression was detected in the brain (C) or corpus callosum (D). BTK IHC staining with hematoxylin and blueing counterstain. [Figure 20] Favorable particle size distribution of nano-sized LOU064. [Figure 21](A) Trough BTK occupancy over 24 hours at steady state. Graph shows median prediction as dots, vertical lines show 95% prediction intervals. (B) Mean BTK occupancy over 24 hours at steady state. Graph shows median prediction as dots, vertical lines show 95% prediction intervals. [Figure 22] Simulation of splenic BTK occupancy at steady state. [Figure 23] scRNA-seq analysis of rat MOG EAE mice treated with LOU064: Neuroinflammatory signatures are significantly downregulated in microglia from the brain and spinal cord of EAE mice treated with LOU064. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0138] definition As used herein, a "BTK inhibitor" refers to an intracytoplasmic tyrosine kinase that is It inhibits Bruton's tyrosine kinase (BTK), a member of the TEC kinase family. BTK is a cytotoxic molecule that inhibits the production of cytotoxic T cells. In cells of the adaptive and innate immune systems, including basophils, and in platelets, Examples of BTK inhibitors include non-covalently binding β-lactams such as fenebrutinib. Reverse BTK inhibitors and evobrutinib, trebrutinib, rilzabrutinib, and tirabrutinib Nib, branebrutinib, orelabrutinib and remibrutinib (LOU064) and covalent irreversible BTK inhibitors.

[0139] As used herein, "LOU064" with INN remibrutinib refers to Structural formula: [ka] The compound having the formula N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) 5-fluoro-2-methylphenyl)-4-cyclopropyloxypyrimidin-4-yl pyr-2-fluorobenzamide, or a pharma- ceutically acceptable salt thereof, or a free form thereof In one embodiment, LOU064 refers to the polypeptide of International Publication No. Crystalline forms of LOU064 disclosed in Example 1 of Patent Publication 2020 / 234779 Refers to the attitude.

[0140] LOU064 is a selective, potent, irreversible covalent BTK inhibitor and a new generation of design It is one of the most well-known covalent enzyme inhibitors (Angst et al. 2020). The compound is disclosed in International Publication No. WO 2015 / 079417 filed on November 28, 2014. This was first disclosed in Example 6 of the brochure.

[0141] The terms "treatment" or "treating" refer to the administration or administration of, e.g., LOU064, to a patient. The purpose of this therapy is to eliminate the symptoms of diseases such as multiple sclerosis (MS). In particular, the term "treatment" refers to the treatment of a patient's Achieving a clinically meaningful response, e.g., when treating RMS, achieving a clinically meaningful outcome This term also includes achieving a reduction in relapse rates during the course of treatment. and

[0142] The term "patient", as used herein, refers to a mammal, such as a primate, preferably a The subject may be a higher primate, and more preferably a human (e.g., a patient at risk, or a subject as described herein). The patient may be a patient at risk of having a disorder that is associated with atherosclerosis. Preferably, the patient is an adult. Typically, patients between the ages of 18 and 60 are preferred, although elderly patients are also included.

[0143] As used herein, it refers to a condition in which a patient is unable to recover medically or in terms of quality of life from such treatment. Such patients may be "in need of" treatment if they would benefit from it.

[0144] As used herein, "administering" LOU064 or "administration of LOU064" refers to The term "providing" refers to providing LOU064 to patients in need of treatment. Administration "in combination with" one or more further therapeutic agents can be in any order and This includes simultaneous (concurrent) and sequential administration, and by any route of administration.

[0145] As used herein, a "therapeutically effective amount / dose" refers to a dose that is effective, i.e., clinically This may refer to the amount / dosage of LOU064 that achieves a clinically meaningful effect.

[0146] The term "adverse event" (AE) refers to any untoward medical occurrence in a patient or clinical trial. The subject may be involved in a clinical trial, where the subject does not necessarily have a causal relationship to the treatment. Therefore, adverse events (AEs) are events related to a drug (investigational drug). Any favorable event that is temporally related to the use of a medicinal product (investigational drug), whether or not related It may be an unexpected and unintended sign (including abnormal laboratory findings), symptom or disease.

[0147] The phrase "therapeutic regimen" or "treatment regimen" refers to a method for treating a disease or condition. or the regimen used to prevent the onset of a disease, e.g., the medication used. The therapeutic or treatment regimen may include induction regimens, loading regimens, and and a maintenance regimen (e.g., a loading dose is an initial dose of the drug, preferably Treatment should be completed before success with a maintenance dose, preferably before rapidly tapering to a lower maintenance dose. A higher initial dose can be given at the beginning of a course of treatment (e.g., DMT).

[0148] As used herein, "multiple sclerosis" refers to primary progressive multiple sclerosis (PPM) S), relapsing-remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS) , particularly in active SPMS (with occasional relapses and / or evidence of new MRI activity), and in Any relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS) This refers to a form of the disease.

[0149] Primary progressive MS (PPMS) is a condition that occurs over a period of time from symptom onset without early relapses or remissions. Characterized by a worsening of neurological function (accumulation of disability). PPMS may occur at different times: , active (with occasional relapses and / or evidence of new MRI activity) or and progression (with or without recurrence or new MRI activity, as determined by changes over time) The disease may be further characterized by evidence of disease progression on objective measures or no progression. Yes, it is possible. See Lublin 2014.

[0150] Each person's experience of PPMS can be unique. PPMS may be characterized by relapses or the presence of new MRI activity. There were short periods of stable disease with or without new recurrences or lesions on MRI. Regardless, there may be periods during which increased disability occurs.

[0151] The term RMS (relapsing multiple sclerosis) is used to refer to RRMS, SPMS, and especially active SPM. S, and CIS.

[0152] Relapsing-remitting multiple sclerosis (RRMS), for example, often does not have fever or infection, but Defined as a new neurological disorder or episode of neurological deterioration lasting longer than 24 hours It is characterized by recurrence.

[0153] During remission periods, there is no obvious progression of the disease. At different times, RRMS may be active active (with recurrence and / or new MRI evidence) or inactive and progressive is worsening (a documented increase in disability over a specified period following a relapse) or Lublin 2014, Neurol. gy:2014 Jul 15;83(3):278-286 is referenced.

[0154] Secondary progressive multiple sclerosis (SPMS) occurs after an initial relapsing-remitting course. Most people diagnosed with S will eventually progress to the secondary progressive process, where There is a progressive deterioration of neurological function over time (accumulation of disability). SPMS is Is it active (with recurrence and / or evidence of new MRI activity) at different time points? or inactive, and progressive (objective measure of change over time, with or without recurrence) The disease may be further characterized as progression (evidence of worsening of the disease in any stage) or lack of progression. Lublin 2014,Neurology:2014 Jul 15;83(3): Please refer to 278-286.

[0155] Each person's experience of SPMS can be unique. SPMS follows relapsing-remitting MS. Disability may persist over time, with or without evidence of disease activity (relapse or changes on MRI). In SPMS, occasional relapses can occur during periods of stability. According to the present invention, the term SPMS particularly refers to active SPMS, i.e. relapsing and / or or SPMS with evidence of disease activity as determined by the presence of changes on MRI Point.

[0156] Clinically isolated syndrome (CIS) is a central nervous system disorder suggestive of multiple sclerosis (MS). CIS symptoms can refer to a single clinical episode of an inflammatory demyelinating condition of the central nervous system (CNS). It can be focal or multifocal and usually involves the optic nerves, brain stem, cerebellum, spinal cord, or cerebral hemispheres. obtain. Miller et al, Clinically isolated synd Romes, Lancet Neurol. 2012;11:157-169 do.

[0157] A relapse is defined as a new neurological deficit or neurological deterioration that preferably lasts longer than 24 hours. In other words, a recurrence preferably lasts for at least 24 hours. A discrete episode of neurological dysfunction (known in the art as an "attack") lasting for 10 minutes or more. "ack," "flare-up," or "exacerbation" Relapses are usually followed by complete or partial recovery and A period of time (remission) follows without progression of symptoms or accumulation of disability.

[0158] Relapses may occur as a result of new or expanding hepatitis at the site of the inflammatory event within the central nervous system (CNS). It is presumed to be caused by medulla.

[0159] Revised McDonald criteria (Thompson et al 2018) Under the revised McDonald criteria, myelopathy was considered to be a rare condition, as seen on MRI: MS can be diagnosed when phosphorus lesions are spatially distributed (DIS): - At least two or four CNS locations: paracortical, periventricular, ricular and infratentorial regions, and at least one bright T2 lesion in the spinal cord T2 is used to diagnose MS and to detect old and new myelin damage in the brain and spinal cord. (This is the most common MRI scan used to detect the area.) - These lesions do not need to be gadolinium enhanced.

[0160] Regarding temporal myelin damage (DIT), MRI evidence is as follows: - Compared to the baseline scan (regardless of time from baseline), New T2 and / or Gadolinium-Enhancing Lesions on Close-Up MRI. 2005 Update required that at least 30 days elapse between the initial and first seizure. - The simultaneous presence of asymptomatic gadolinium enhancing and nonenhancing lesions at any time point.

[0161] Primary progressive MS (PPMS) has special diagnostic needs. The proposed McDonald criteria require at least one year of demonstrated progress (either prospectively or retrospectively). In addition to a clinical evaluation (performed retrospectively), two of the following three findings are required: - T2 in at least one of the three key brain regions (periventricular, paracortical or infratentorial) Evidence of DIS in the brain seen in lesions. - Intraspinal DIS based on at least two T2 lesions DIS (≥2 T2 lesions) Evidence of. - As seen in the presence of oligoclonal bands and / or high IgG index , positive CSF involvement.

[0162] Gd+ lesions Gadolinium (the "contrast agent") is a chemical compound that is injected into a person's veins during an MRI scan. Gadolinium is normally unable to enter the brain or spinal cord from the bloodstream due to the blood-brain barrier. No. However, during active inflammation in the brain or spinal cord, such as during a relapse of MS, blood The brain barrier is destroyed, allowing gadolinium to pass through. Gadolinium then enters the brain or It enters the spinal cord, leaks into MS lesions, and emits light, creating highlighted spots on MRIs. Such MS lesions are called gadolinium-enhancing lesions or Gd+ lesions. .

[0163] T1 and T2 Lesions T1 and T2 refer to different MRI techniques used to generate magnetic resonance images. Specifically, T1 and T2 refer to the time taken between the magnetic pulse and the recording of the image. These different methods are used to detect different structures or chemicals in the central nervous system. T1 and T2 lesions were classified according to whether the lesion was detected using the T1 or T2 technique. T1 MRI images highlight areas of active inflammation, helping to clarify current disease. T2 MRI images provide information about disease burden or lesion burden (old disease The study provides information on the total area of ​​lesions (both new and changed lesions).

[0164] EDSS The Expanded Disability Status Scale (EDSS) quantifies disability in multiple sclerosis and This is a method of monitoring changes in injury levels over time.

[0165] The EDSS scale ranges from 0 to 10, with increments of 0.5 units representing higher levels of disability. Scoring is based on examination by a neurologist.

[0166] EDSS steps 1.0 to 4.5 indicate patients with MS who can walk without assistance. is based on measures of impairment in eight functioning systems (FS): Pyramidal function – muscle weakness or difficulty moving the limbs Cerebellar function – ataxia, loss of balance, coordination or tremors Brain stem function – problems with speech, swallowing and nystagmus Sensory function – numbness or loss of sensation Bowel and bladder function Visual function - problems with vision Cerebral function – problems with thinking and memory · others.

[0167] Functional systems (FS) represent neuronal networks in the brain that are responsible for specific tasks. Each FS is scored on a scale from 0 (no disability) to 5 or 6 (more severe disability). Kurtzke JF.Rating Neurologic Impairment Ent in Multiple Sclerosis:An Expanded Di ability status scale(EDSS).Neurology:19 83,Nov;33(11):1444-52.

[0168] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 version 2 contains 29 items, including two domains: physical and psychological. The questionnaire is self-administered. Responses are on a four-item scale ranging from 1 (not at all) to 4 (extremely). It was recorded on an ordinal point scale, with higher scores indicating greater impact on daily life. MSIS-29 takes about five minutes to complete and questions are asked about your daily routine over the past two weeks. It is designed to determine patients' views of the impact of MS on their lives. rt J and Cano S (2009), “Improving the eva luation of therapeutic interventions in multiple sclerosis: the role of new psych metric methods”,Health Technol Assess;1 3(12):iii,ix-x,1-177.NS RO,to Hobart J,L amping D, Fitzpatrick R, et al (2001), “The Multiple Sclerosis Impact Scale (MSIS-29) :a new patient-based outcome measure”,Br ain;124(Pt 5):962-73.

[0169] SDMT or symbol-digit modality is typically affected in cognitively impaired MS participants. It is a sensitive and specific test for assessing processing speed in the brain (Benedict et al. al.2017,Mult Scler;23(5):721-733). Test scores Rings are calculated by the number of correct answers in 90 seconds (highest is 110, lowest is zero). A higher score indicates improvement and a lower score indicates deterioration.

[0170] T25FW or Timed 25-foot Walk is the timed 25-foot walk test that The T25FW is the time to a 20% or greater deterioration in neurological function that persists for 6 months. It is a quantitative test (Fischer et al 1999, Multi Scler; 5: 244-50), is widely used in clinical MS trials to assess gait. A walking test is used to evaluate walking speed, which is the time it takes to walk 25 feet (7.62 meters) in seconds. A 20% improvement is when the time (seconds) is increased. It is defined as being 20% ​​shorter.

[0171] The 9HPT or 9-Hole Peg Test (9HPT) is an objective quantitative test of neurological function. (Fischer et al.1999 Mult Scler;5:244-50) , which is widely used in clinical MS testing to assess dexterity. It is used to measure the dexterity of the right and left arms. Both are measured to assess the score, and the metric is the number of steps required to insert and remove the nine pegs. The time required (in seconds).

[0172] Nfl, or neurofilament light chain (NfL), is a component of the neuronal cytoskeleton and is involved in axonal injury. After injury, it is released into the cerebrospinal fluid and then into the blood. This is related to disease activity (Kuhle et al. t al 2019,Ann Clin Transl Neurol;6(9):17 57-1770), disease monitoring (Akguen et al 2019, Neuro ol Neuroimmunol Neuroinflamm;6(3):e555), Treatment response (Hauser et al 2020, N Engl J Med;546- 557) as a biomarker for disease activity and physical activity in participants with MS It has been identified to predict the worsening of disability (Barro et al. 2018, Bra in 141:2382-2391, Kuhle et al 2019, Kapoor et al 2020 Neurology;95(10):436-444, Jak imovski et al 2019 Ann Clin Transl Neuro l;6(9):1757-1770).

[0173] The GAD-7 or Generalized Anxiety Disorder-7 is a 7-item self-assessment scale (Spitzer According to et al 2006,Arch Intern Med;166:1092-7 The scale was developed by the National Institute of Mental Disorders (NIMD) and is used as a screening tool and severity index for GAD. Response options are a 4-point Likert scale: 0: never; 1: several days; 2: more than half the days; 3: Almost every day. Has a global score ranging from 0 to 21. Higher scores indicate This means that the severity of anxiety symptoms is greater.

[0174] The PHQ-9 or Patient Health Questionnaire-9 is a reliable and valid 9-item questionnaire from the full PHQ. This self-administered tool is used to screen for the severity of depression, It is used to diagnose, monitor and measure depression based on criteria. It is used to make the cuts (Kroenke et al 2001, J Gen In tern Med;16:606-13).

[0175] PHQ-9 scores range from 0 (not at all) to 3 (almost every day) for each of the nine items. The range of scores can be 0 to 27. Q-9 scores represented mild, moderate, somewhat severe, and severe depression, respectively.

[0176] The BPI-SF or Brief Pain Inventory-Short Form is a shorter version of the Brief Pain Inventory (15 items). (Cleeland and Ryan 1994, Ann Acad Med; 23(2):129-59), which evaluates the severity of pain and its impact on daily functioning. It is used to evaluate pain severity, pain location, analgesics, and pain relief over the past 24 hours. Along with the amount of pain, the BPI-SF measures how pain affects general activities, mood, walking, work, and relationships with others. A seven-item interference scale was also administered to assess the extent to which the disorder interfered with sleep, activities, and enjoyment of life. Includes 10-point response options ranging from 0 (not interfering) to 10 (completely interfering). Global scores range from 0 to 10, with lower scores indicating less pain. represent.

[0177] The FSIQ-RMS™ or Fatigue Syndrome and Impact Questionnaire-Relapsing Multiple Sclerosis is Measures the symptoms and impact of fatigue in the RMS. This reliable and valid tool consists of two Symptom domains (vitality, muscle weakness) and seven impact domains (daily activities, cognition, emotion, physical The questionnaire includes 20 items, including symptoms, self-care, sleep, and social impacts. 24 hour and 7 day recall period to capture impact. Domain and subdomain The FSIQ-RMS score by the score of the individual. The global score ranges from 0 to 100. , with higher scores representing greater fatigue (Hudgens et al. 2019, Value Health;22:453-466).

[0178] The HUI-III™ or Health Utility Index™ is a health indicator that measures health status and provides health-related A general health profile and preferences for reporting quality of life and creating a utility score It is a group of systems based on the 0(22):113-28). The HUI-III measures vision, hearing, speech, and locomotor / mobility. It measures eight HRQoL domains, including pain, dexterity, emotion, and cognition. The study conducted a self-report version in which participants reported their “usual health status” for a recall period. The HUI questionnaire responses are then mapped to specific levels. The HUI-III has the following domains (levels for each domain): Vision (Level 6) Hearing (Level 6) Speech (Level 5) Locomotor Movement (6 levels) Dexterity (6th level) Emotions (5 levels) Perception (6 levels) Pain (5 levels) A decrease in the HUI score means the condition has worsened.

[0179] Disease Modifying Therapy (DMT) The term "disease-modifying therapy" refers to the fact that there is no curative treatment for multiple sclerosis (MS) yet. However, several disease-modifying drugs (DMDs) have been approved for MS and may be used. In general, DMTs for RMS reduce the frequency and / or severity of relapses. So, DMT is not a cure for RMS sufferers, but it can help to reduce the number of times someone relapses and how many DMTs include interferon beta, glial acetate, mer, teriflunomide, mitoxantrone, dimethyl fumarate, cladribine, fingolimod Rimod, siponimod, ponesimod, alemtuzumab, daclizumab, natalizumab, off Treatment with DMD, such as rituximab, ocrelizumab, and rituximab, is included. The present invention is not limited to these.

[0180] According to the present invention, DMTs are used when the progression of the disease is not stopped or adequately slowed. This may be due to, for example, the fact that patients receiving DMTs may relapse or develop This is the case when patients show signs of disease activity such as changes in blood pressure.

[0181] According to the present invention, "lack of tolerance" to DMT can be attributed to headaches, dizziness, nausea, infections (shingles), ), and are associated with the presence of adverse events such as macular edema, infusion-related reactions, or recurrent infections.

[0182] B cell depletion therapy As used herein, the term "B cell depletion therapy" refers to anti-CD20 mAb-based B cell depletion therapy. Any cell depletion therapy that results in depletion of B cells, including CD19 / CD20 depletion therapy. In particular, in anti-CD20 mAb-based B cell depletion therapy, B cell depletion is , monoclonal antibodies targeting CD20-expressing B cells, e.g., alemtuzumab, dacl, Administration of rituximab, natalizumab, ofatumumab, ocrelizumab, and rituximab This is achieved.

[0183] loading dose A loading dose is an initial dose of a drug, preferably administered before a maintenance dose is administered successfully. Administered at the beginning of a course of treatment (e.g., DMT) before being rapidly tapered to a lower maintenance dose The initial higher doses that can be achieved are:

[0184] Neurologically stable A clinical condition characterized by an absence of alteration in mental status or level of consciousness. control of new neurological deficits, e.g., aphasia, ataxia, dysarthria, paresis, paralysis, This may include the absence of visual field defects or blindness and is defined as being neurologically stable.

[0185] rebound Severe disease reactivation after DMT withdrawal that exceeds a patient's pre-DMT baseline is This is considered a bounding event. Barry et al., Fingolimod Reb ound:A Review of the Clinical Experience and Management Considerations.Neurol Th Please refer to er(2019)8:241-250.

[0186] Breakthrough Disease For purposes of the present invention, breakthrough disease is defined under the DMT as follows: : At least one documented recurrence in the past year or two recurrences in the past two years; the presence of at least one Gd+ lesion on an MRI scan within the past 12 months; and / or Presence of new or enlarging T2 lesions within the past 12 months

[0187] As used herein, a "B cell inhibitor" generally refers to an agent that abolishes or reduces biological B cell function. B cell inhibitors can refer to any substance that reduces or attenuates biological B cell functions. functions, e.g., cytokine secretion, or response to cis and / or trans stimuli. B cell inhibitors can block signaling pathways that inhibit the production of B cells from stem / progenitor cells. In addition, B cell inhibitors can block the production of or adversely affect the maturation of T It may act by inhibiting crosstalk with other cell populations, such as cells. B cell inhibitors may be secreted by sequestration (e.g., in lymphoid tissues such as the spleen) or by lysis. and depleting B cells, for example through CDC, ADCC, phagocytosis, or other processes. Some subsets of B cells can express CD20.

[0188] As used herein, B cells may refer to a type of white blood cell of the lymphocyte subtype. They act as regulators of the adaptive immune system by secreting antibodies, such as immunoglobulins (e.g., IgG). They function in the humoral immune component. In addition, B cells present antigens and secrete cytokines. B cells, unlike T cells and natural killer cells, have a B cell receptor on their cell membrane. B cells express the BCR, a receptor for antigens that bind to specific antigens to initiate an antibody response. This makes it possible to do so.

[0189] As used herein, a T cell inhibitor is an inhibitor of a biological T cell function that abolishes, reduces and / or inhibits T cell inhibitors can refer to any substance that attenuates biological T cell function, e.g. For example, signals required for cytokine secretion or response to cis and / or trans stimuli. T cell inhibitors can block the null signaling pathway and inhibit the generation of T cells from stem / progenitor cells. In addition, T cell inhibitors may interfere with or adversely affect the maturation of B cells. Alternatively, it may act by inhibiting crosstalk with other cell populations. Inhibitors may be released into the body by sequestration (e.g., in lymphoid tissues such as the spleen) or by lysis, e.g. For example, T cells can be depleted via CDC, ADCC, phagocytosis, or other processes. .

[0190] As used herein, T cells can refer to a type of lymphocyte that develops in the thymus. T-cells can be distinguished from other lymphocytes by the presence of T cell receptors on the cell surface. EXAMPLES

[0191] Example 1 Bruton's tyrosine kinase (BK) expression in human MOG-induced experimental autoimmune encephalomyelitis TK) inhibitor LOU064 There are no known naturally occurring MS-like diseases in rodents or non-human primates. The antibody was sensitized by CNS-specific myelin proteins emulsified in soluble adjuvant (CFA). Induced disease models are developed after immunization of male rodent strains. Experimental autoimmunity Encephalitis (EAE) is a common pathological phenotype of MS that involves extreme demyelinating lesions of the CNS white matter. In C57BL / 6 mice, human (human MOG) or rat (rat MOG ) Depending on which recombinant protein sequence is used, the myelin oligodendrocyte There are two variants of mouse endocrinopathy glycoprotein (MOG)-induced EAE (Lyons JA .et al.(1999)European Journal of Immunol ogy 29:3432-3439;Oliver ARet al.(2003) J Immunology 171:462-468). As a result, human MOG-induced EAE is highly dependent on B cells as APCs, whereas rat MOG-induced EAE is highly dependent on B cells as APCs. G-induced EAE is B cell independent and requires dendritic cells as the major APC population ( Lyons et al 1999;Molnarfi N. et al.(2013) Journal of Experimental Medicine 210(13) :2921-2937).

[0192] In human MOG-induced EAE, the BTK inhibitor LOU064 was administered for 12 h at 1 day intervals. LOU064 was administered twice (bid) at either 3 mg / kg or 30 mg / kg. Prophylactic dosing began 6 hours before MOG / CFA immunization and continued until the end of the study.

[0193] EAE was assessed using the scoring system outlined in Table 1. Throughout the experiment, Clinical scores and body weights were assessed daily. Prior to the start of treatment, all groups were evaluated for clinical profile and Animals were randomized to be comparable for body weight.

[0194] [Table 1]

[0195] In accordance with animal regulations, the humane end point for EAE mice is a score of 3 (>7 days), a score of 3.5 (>3 days) or reached a score of 4 and was immediately terminated.

[0196] LOU064 (30 mg / kg orally bid) inhibited inflammation-induced cachexia. The compound significantly reduced the clinical symptoms of EAE in all animals (Figure 1). It was tolerated.

[0197] Additional analyses showed that the efficacy of LOU064 was associated with a reduction in the frequency of EAE episodes. , revealing that many animals were completely protected from disease (Figure 2).

[0198] BTK inhibition also reduced group EAE scores (peak neurological paralysis) and It also reduced the overall disease burden (Figure 3).

[0199] Concentrations of LOU064 present in blood 1, 5, and 8 hours after bid administration of the compound. The levels are shown in Table 2. Blood exposure was at the expected level at 1 hour, and at 5 and 8 hours. The effect decreased rapidly over time and was dose-related at doses of 3 to 30 mg / kg bid. Compound levels in whole brain homogenates were very low and were detected primarily at early time points. Similarly, levels in cerebrospinal fluid (CSF) are low.

[0200] [Table 2]

[0201] Blood, brain and CS of LOU064 after oral administration of 3 and 30 mg / kg bid F levels. The LLOQ was 0.2 nM in blood and 0.5 pmol / L in brain homogenates. g and 0.5 nM in CSF. At 1 h, mean ± S from 4 animals D, Means ± SD from three animals are shown for the 5 and 8 h time points. a Shown together with Where applicable, values ​​were obtained from one animal out of three that was above the LLOQ.

[0202] BTK expression in the spleen was measured 1, 5, and 8 hours after bid oral administration of LOU064. The prevalence of BTK in the spleen was determined (Figure 4). BTK occupancy in the spleen was greatest at both doses, with BTK occupancy at 3 mg / kg. The occupancy rate was attenuated after administration of 100 mg / kg and more sustained after administration of 30 mg / kg. These BTK occupancy levels were comparable to other studies performed in mice.

[0203] BTK occupancy in the inguinal lymph nodes is shown in Figure 5. BTK occupancy was maximal at both doses. The effect was attenuated after 3 mg / kg administration and more sustained after 30 mg / kg administration. These BTK occupancy levels were measured in mice with LOU064. This was comparable to other studies.

[0204] BTK occupancy was assessed in brain homogenates prepared for compound exposure analysis ( (Figure 6). The dose group receiving 30 mg / kg bid LOU064 showed the greatest BTK occupancy. The 3 mg / kg dose showed minimal inflammatory bowel movement at 1 hour, which decreased over the dosing interval. The variability in brain BTK occupancy was only measured by compound-level evaluation. This may be due to the fact that the analysis was performed on the remainder of the homogenate prepared for .

[0205] Ex vivo analysis of MOG-specific antibody responses in serum revealed a small, but statistically significant, A significant decrease in IgM and IgG levels was observed in the human MOG-induced E In AE models, (auto)antibody responses are weakly pathogenic. The discrepancy between B cell antigen presentation and the body's very subtle regulation of neuroinflammatory processes This suggests that.

[0206] Using a brief 8-day (pre-disease) EAE protocol, we investigated immune profiling in the human MOG model. The mechanism of weight gain was investigated. Prophylactic treatment with LOU064 improved weight gain. These results suggest that inflammation-induced cachexia is regulated in this model. As previously mentioned, no adverse events were observed in any of the dose groups.

[0207] Ex vivo M We investigated OG-induced recall proliferation responses. In vivo treatment resulted in the induction of both immune cell compart- ments. In contrast, a dose-dependent decrease in proliferation occurred in the lymph node cells (Figure 9). Plate-bound anti-CD3 / CD28 polyclonal stimulation is affected by in vivo treatment These data suggest that specific inhibition of B cell antigen-presenting function, rather than broad immunosuppression, is the cause. This suggests that...

[0208] Ex vivo analysis of isolated splenocytes, lymph node cells, and blood demonstrated potent expression of IFN-γ in all B cell populations. No significant changes were observed (Figure 10). Analysis of CD4+ T cells revealed that LOU064 treatment It was subsequently revealed that only the Th17 population was reduced, while Th1 and regulatory T cells remained unchanged. It became.

[0209] We need to further clarify whether the efficacy of BTK inhibitors is directly related to the reduction of B cell antigen-presenting function. To clarify this, the compounds were tested in a recombinant rat MOG-induced EAE model. The EAE model shares many of the characteristics of recombinant human MOG-induced EAE, Antigenic T cells infiltrate the CNS and cause neurological paralysis. Pathogenic EAE is B cell independent, with dendritic cells being the major antigen-presenting cell type. BTK inhibitors are not associated with a broader, nonspecific immune suppression in rats, unless drug treatment is associated with a broader, nonspecific immune suppression. It can be predicted that there will be no significant efficacy in mouse MOG-induced EAE. In addition to LOU064, which was used at 10 mg / kg and 1 g / kg, the reference compound Ibrutinib was Cyclosporine A (CsA) was used as a positive control for direct T cell immunosuppression. Using a short (pre-disease) EAE protocol of 8 days, the rat MOG model We investigated the immune priming mechanism in the treatment of BTK. No adverse events were observed with either BTK inhibitor. Using isolated splenocytes harvested 8 days after immunization, MOG-induced The recall proliferation response was studied. In vivo BTK inhibitor treatment affected the recall response. In contrast, CsA significantly inhibited T cell recall proliferation. The data suggest that BTK inhibition-mediated immune regulation is highly selective and targets (auto)immune priors. These results suggest that the IL-1 signaling pathway is directly related to B cells that function as antigen-presenting cells during the IL-1 signaling step.

[0210] Conclusion and Discussion These studies utilized two separate EAE models in C57BL / 6 mice. The recombinant human MOG-induced EAE model is B cell dependent and depletion of anti-CD20 B cells Although the rat MOG-induced EAE model is sensitive to B cells, it is not dependent on dendritic cells. They function as important antigen-presenting cells.

[0211] Unexpectedly, LOU064, a small molecule irreversible (covalent) inhibitor of BTK, inhibited the human MO The results demonstrated that the drug is highly effective in inhibiting the induction of G-induced EAE. The efficacy of BTK in treating inflammation-induced cachexia was confirmed by sustained high levels of BTK occupancy in tissues. Mechanistically, the experimental findings suggest that B cell-dependent immune responses during the immune priming phase Consistent with the suppression of dependent (self) antigen presentation, this reduces the frequency of pathogenic Th17 cells. The discrepancy between the validity of the clinical score and the slight decrease in (auto)antibodies indicates that this is an important pathogenesis. This suggests that it is not a mechanism.

[0212] Evidence from a rat MOG-induced EAE model shows that BTK inhibition at the immune priming stage It was shown that the BTK inhibitor (L OU064) Conclude that efficacy is not the result of broad (non-selective) immunosuppression is possible.

[0213] In conclusion, LOU064, a covalent BTK inhibitor, surprisingly inhibits human multiple myeloma. Unexpectedly beneficial against a pathogenic process known to be highly relevant to the treatment of sclerosis The present invention has demonstrated a highly selective mechanism of action that results in favorable and superior efficacy.

[0214] Example 2 Bruton's tyrosine kinase (BK-TKI) expression in rat MOG-induced experimental autoimmune encephalomyelitis BTK inhibitor LOU064 Pharmacological inhibition of BTK or genetic deficiency of BTK has been reported to ameliorate preclinical mouse EAE. It has been reported that BTK inhibitors are effective due to their effects on B cells and myeloid cells. It is suggested that this can be achieved (Torke S. & Weber MS (2020) Expert Opinion on Investigational Drugs 29:1143-1150;Mangla A.et al.(2004)Blood 104(4):1191-7, and Example 1). Previous studies with LOU064 have shown that The focus has been on the cellular-driven experimental autoimmune encephalomyelitis (EAE) model. (Example 1) This study demonstrated that LOU064, possibly through its effects on myeloid cells, To demonstrate efficacy in rat MOG-EAE that is independent of B cells We extend this evidence further by

[0215] LOU064 treatment reduced the incidence of EAE In rats with MOG-induced EAE, the BTK inhibitor LOU064 was administered at 8 / 16 hour intervals. LOU064 was administered twice daily (bid) at 30 mg / kg in the presence of Treatment was started 4 hours before G / CFA immunization and continued twice daily until the end of the study. The compound inhibited the inflammation-induced clinical symptoms and cachexia of EAE (Figure 13). The drug was well tolerated in mice.

[0216] Additional analyses demonstrated the efficacy of LOU064 in reducing the incidence and delaying the onset of EAE. This is associated with a high degree of disease severity, with many mice being completely protected from disease by the end of the study (Figure 14). It was revealed that (p value = 0.018).

[0217] BTK inhibition also reduced the group EAE scores (peak neurological paralysis p value) over the entire experimental period. = 0.069) and total disease burden (p-value = 0.013) were also significantly reduced (Figure 15).

[0218] LOU064 treatment reached its pharmacological target FIG. 16 shows the spleen, blood and Final BTK occupancy in the brain is shown. Trough BTK occupancy levels in the spleen and blood were , which is within the range indicating maximum BTK occupancy upon peak LOU064 exposure. It was shown that when exposure to β-lactams decreased, the resynthesis of free BTK was affected (Angeste These BTK occupancy levels were consistent with previous studies conducted in mice. was equivalent to.

[0219] BTK occupancy assessed in brain homogenates showed intermediate levels and was potent at peak blood exposure. Significant (p-values ​​<0.001 for spleen, blood and brain), but possibly submaximal brain B It was suggested that TK occupancy was achieved.

[0220] LOU064 treatment did not affect autoantibody levels FIG. 17 shows the MOG-specific autoantibody levels in serum 16 hours after the last administration on the final day (day 21). Autoantibody levels in immunized mice treated with either vehicle or LOU064. The MOG-specific autoantibody levels, total IgM and IgG subclasses were significantly higher in naive and control mice. LOU064 treatment significantly increased serum These results were consistent with those of the above experimental results. This is consistent with what was observed in the human MOGEAE model, as described in Example 1.

[0221] LOU064 treatment tended to decrease serum NF-L levels FIG. 18 shows the levels of NF-L in serum. In immunized mice, the mean NF-L levels were significantly higher compared to naive mice. Furthermore, the vehicle-treated group showed a significant correlation between the increase in clinical scores and serum NF-L levels. A significant association was observed in the LOU064-treated group (p-value = 0.0006), which was not observed in the vehicle-treated group. The trend for decreased mean NF-L levels was not significant compared to the ALK-treated group.

[0222] Evidence for BTK expression in tissues by IHC FIG. 19 shows the results of the ELISA in lymph nodes (positive control; A and B) and brains (C and D) of naive mice. Representative examples of IHC staining for BTK expression in mice are shown. K is a B-cell follicle in the lymph node (A), particularly some scattered throughout the paracortex of the lymph node. In the naive mouse brain, BTK was detected in the corpus callosum, and in the cells that express it. (C and D).

[0223] Conclusion and Discussion The primary goal of this study was to identify a potent and selective BTK inhibitor in a B cell-independent EAE model. The aim of this study was to evaluate the efficacy of a covalent inhibitor (LOU064) for L OU064 was given at a dose of 30 mg / kg bid and was completely expressed in the blood and spleen. Total BTK occupancy was demonstrated, but in the brain, only partial BTK occupancy was demonstrated.

[0224] The results show that LOU064 affects parallel IgM and IgG responses. showed that the compound was indeed effective in reducing the severity of MOG-induced EAE in rats. vinegar.

[0225] Overall, these results are independent of its ability to inhibit BTK in B cells. , showing the therapeutic efficacy of LOU064. It is known that lineage cells also express BTK (Torke et al., 2020). Therefore, the model used allows us to suspect an important pathogenic role for these cells. This is consistent with recent preclinical and clinical observations, which suggest that peripheral inflammatory pathways may be important for controlling CNS inflammation. It clearly shows beneficial effects in targeting myeloid cells (Ifergan I. and M iller SD(2020)Front Immunology 11:5718 97).

[0226] The basis for the efficacy of LOU064 in this study using the rat MOG EAE model The driving force could be inhibition of myeloid-type BTK-expressing peripheral immune cells such as macrophages, but the Unexpectedly, the level of BTK occupancy detected in the brain may also contribute to the overall efficacy of treatment. Histological analysis revealed no BTK expression in the brains of healthy mice. Therefore, the BTK occupancy levels measured in the brains of EAE mice were consistent with those in BTK-expressing cells. It can be concluded that these findings reflect EAE-induced CNS infiltration due to EAE.

[0227] This study does not show an effect of LOU064 on EAE-induced IgM / IgG responses. This fact is consistent with previous observations regarding the level of anti-MOG antibody responses (Example 1). In theory, the covalent BTK inhibitor LOU064 may be a promising candidate for the treatment of multiple sclerosis in humans. It has demonstrated unexpectedly superior efficacy against pathogenic processes known to be associated with it. Particularly favorable results surprisingly translate to a human dose of 100 mg bid. This was achieved with an EAE dosage of 30 mg / kg bid.

[0228] Example 3: Brain penetration of LOU064 Passive permeability assay using canine P-gp knockout MDCK cell monolayers (MDCK-LE V2) Transsexual measurement Passive permeation of drug candidates in relation to gastrointestinal absorption using cell-based assays The endogenous canine Mdr1 (cMdr1) gene encoding P-gp was knocked out. MDCK cell lines that have been outgrown are grown in 96-well Transwell plates. Compounds were applied to the apical surface of three cassettes at a concentration of 10 μM each. After loading into the compartment and incubation for 2 h, the phenotypes appearing in the basal chamber were The amount of product is quantified by tandem mass spectrometry.

[0229] In particular, knocking out the endogenous canine Mdr1 (cMdr1) gene suppressed MD We developed a CK cell line. We used a subclone of this cell line to generate a 37 A set of commercially available compounds was used to correlate passive permeability with absorption rates in the human intestine. Based on the Papp measured by the assay, the rate of absorption in humans can be estimated. do.

[0230] method The samples were subjected to RapidFire / MS / MS and LC / MS / MS analysis. Rapidfire and LC / MS / MS conditions are described below. Mass spectrometer: Sciex QTRAP5500 Autosampler: Shimadzu SIL-30ACmp HPLC pump: Shimadzu LC-30AD Column: Phenomenex Kinetex Polar C18 2.1x30m m, 2.6 μm Oven temperature: 50℃ Injection volume: 2μL injection Mobile phase A: Water containing 0.1% (v / v) formic acid Mobile phase B: acetonitrile containing 0.1% (v / v) formic acid and 4% (v / v) water

[0231] [Table 3]

[0232] Detector: SCIEX API5500 QTrap Parameters: Source:ESI Ion spray voltage: 4500V (-4500V in negative mode) Ion source gas 1: 60 psi Ion source gas 2: 40 psi Temperature: 450℃ Curtain gas: 30psi Collision gas: 9psi

[0233] Parent mass, product mass, declustering potential (DP), collision energy (CE), etc. All MS parameters were automatically adjusted using the DiscoveryQuant-O Acquired using ptimize. Scan time is 0.025 seconds.

[0234] A faster alternative to classical HPLC front-end instruments is the C4 (RFCP4A) RapidFire 360 ​​system with cartridges (Agilent Tech The device is coupled to a tandem mass spectrometer in a manner similar to HPLC. Rapid Fire performs solid phase extraction with minimal chromatography. This approach is much faster than conventional LC, but the LLOQ can be increased. Some compounds are not retained well on the cartridge, so some compounds are not classically Reprocessing using a more suitable LC approach may be necessary.

[0235] RapidFire parameters: RapidFire: Agilent RF360 parameters: RapidFire Cycle Duration: Suction: 500ms (approx. 20μL) Load / wash: 4000 ms, flow rate 1.5 mL / min, using 0.1% (v / v) formic acid in water Elution: 3000 ms, flow rate 1.0 mL / min, 0.1% (v / v) formic acid in acetonitrile Use Re-equilibration: 500 ms, flow rate 1.25 mL / min, using 0.% (v / v) formic acid in water RapidFire Cartridge Column Type: C4 (RFCP4A)

[0236] result For LOU064, with high recovery in the MDCK transwell assay, A high permeability of Papp=37.3 was found.

[0237] Example 4 Safety of LOU064 The safety of LOU064 was evaluated based on Phase I and Phase II pharmacokinetic and clinical pharmacological Studies of patients with MS and conditions other than MS, especially chronic spontaneous urticaria (CSU) and Sjögren's syndrome (SJS) The study was conducted in a Phase II / III clinical study in patients with SjS.

[0238] Short-term safety of LOU064 in a Phase I clinical study Dose ranges from 0.5 mg to 600 mg for up to 18 days, as well as 100 and 200 mg bid as single or multiple doses for up to 12 days The short-term safety of LOU064 was demonstrated in a Phase I clinical study (Kaul, M. et al. (2021).Remibrutinib(LOU064):A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial.Clinical and Translational Science.10.1111 / cts.13005 ).

[0239] Summary of safety and tolerability from a Phase 2b study in CSU subjects (interim results) In a dose-ranging study conducted in CSU subjects, the following doses were administered over a 12-week period: Tested: 10, 35 and 100mg qd, 10, 25 and 100mg bi .d. as well as placebo.

[0240] LOU064 was well tolerated across the entire dose range, with most AEs being mild in severity. Serious and most common AEs were are listed in Table 3 by preferred term and primary organ system class. 58.1% of patients receiving any dose of LOU064 had at least one AE: 38.6% of patients receiving LOU064 had mild AEs and 16.9% of patients had moderate AEs. In the placebo group, 42.9% of patients had AEs, and 2.6% of patients had severe AEs. % reported at least one AE: 33.3% of patients receiving placebo had a mild AE 9.5% had moderate AEs and 0.0% had severe AEs. Serious AEs occurred in 5 patients (1.9%) receiving any LOU064 dose. ) compared with none in patients receiving placebo (0.0%) : Renal abscess was reported by one patient, leading to discontinuation of treatment (day 29, 25 mg b. id); one patient reported worsening lymphadenopathy (present before the start of the study but persisting until 1 worsened on day 2, 10 mg qd); one patient had no treatment during follow-up Ureteral stones were reported on day 87 (10 mg bid); two patients had CS One patient experienced U relapse / progression (day 30, leading to discontinuation, 10 mg bid, 1 For humans, 25 mg bid on the 5th day.

[0241] Infections and infestations were the most common AEs by primary system organ class, with 24.0% of patients receiving any LOU064 dose compared with 24.0% of patients receiving placebo Headache (9.7% at either LOU064 dose vs. 14% at placebo) .3%) and nasopharyngytis (8.6% vs. 7.1%) It was the most frequently reported AE (occurring in ≥10% of patients in any treatment group) .

[0242] Overall, 2.6% (n=7) of patients receiving any LOU064 dose experienced Patients with refractory bronchitis had AEs leading to discontinuation in 0.0% of patients treated with placebo (n=0). There were no significant laboratory findings, including blood counts, in any of the study groups.

[0243] Analysis of the laboratory data revealed no significant findings. Overall, the AE common terminology There were three events of grade 3 (none higher), all asymptomatic and without medical intervention. One patient experienced an increase in creatinine 8 weeks after starting the ketogenic diet. (10 mg qd); values ​​normalized after cessation of the ketogenic diet. In patients with a history of pulmonary tuberculosis, the neutrophil count decreased by one at week 12 (35 mg qd). values ​​improved during the treatment-free follow-up period. At week 8, alanine transaminase There was one elevation (100 mg qd); values ​​returned to normal while on treatment.

[0244] [Table 4]

[0245] [Table 5]

[0246] Summary of safety in the Phase 2b study (extension phase) in CSU subjects (interim results) Long-term safety and tolerability studies of LOU064 in eligible CSU subjects enrolled in a Phase 2b study In a 52-week open-label extension study to evaluate tolerability, the dose used was 100 mg. It was a bid.

[0247] At least one episode with a median exposure of 17.86 weeks (range, 2.9 weeks to 44.7 weeks) Safety signals based on interim analysis of 100 subjects treated with LOU064 At the time of cutoff, 93 subjects (93%) were ongoing, Seven subjects discontinued the study; none of the discontinuations were due to adverse events. Table 4 summarizes the safety observed in the phase 2b study up to the cutoff date for the interim analysis. Shows.

[0248] [Table 6]

[0249] Fifty-eight subjects (58%) experienced at least one treatment-emergent AE. The majority of AEs were not serious, did not lead to treatment discontinuation, and were mild in severity. The most frequently affected SOC was infections and infestations (14%), followed by skin and subcutaneous tissue The most common adverse events were tissue disorders (13%) and no trends for specific adverse events. The basic terms (more than 2%) of the elephants are headache (6%), diarrhea (4%), dizziness (3%) and gastroenteritis (3%). %); bleeding events (abnormal platelet aggregation, decreased platelet aggregation, platelet aggregation inhibition, platelet mechanism Haemorrhage SMQ and PT events, including impaired function, abnormal platelet function tests, and platelet toxicity No events were reported in the SOC for hematologic, metabolic, or neurologic disorders (defined as anaphylactic shock syndrome or nausea, vomiting, or vomiting). Three SAEs were reported: ovarian cyst, chest pain, and appendicitis; none were related to the study drug. It was not considered.

[0250] Conclusions from the Phase 2b study and corresponding open-label extension study In summary, the Phase 2b study demonstrated new or unexpected benefits across all doses evaluated. There were no safety findings. In addition, The corresponding CSU extension study included 10 patients enrolled as of August 31, 2020. No safety signals were observed in 0 subjects. LOU064 bid was well tolerated and had a favorable safety profile. It is thought that.

[0251] Summary of safety in Phase 2b study (extension phase) in CSU subjects (Interim results / 35.14 (patients with intermediate exposure of 1 week) In eligible CSU subjects enrolled in a Phase 2b study at a dose of 100 mg bid The 52-week open-label extension study will evaluate the long-term safety and tolerability of LOU064 in The study included a new interim analysis of patients (N=183) who received an interim exposure of 35.14 weeks. The results were compared between the groups of 10 mg qd (once a day), 35 mg qd, and 1 00mg qd, 10mg bid (twice daily), 25mg bid, or 100mg g bid or placebo (1:1:1:1:1:1:1:1) for up to 12 weeks (wks) Safety in a randomized, double-blind, placebo-controlled, Phase 2b core study in adult patients with chronic spondylolisthesis syndrome (CSSU) The results were compared with those of NCT03926611 (Table 5).

[0252] Long-term exposure to ES (median 35.14 wks, N=183) was associated with remibrutinib treatment The proportion of patients with at least one adverse event (AE) (57.4% [n=105]) was , CS (presented for any remibrutinib dose) (58.1% [n = 155]; The median mean time to presentation was 12.14 wks, N=267). In ES, there were four serious adverse events. There were no serious adverse events (SAEs), six AEs led to treatment discontinuation, and no deaths. Reported primary organ class (S OC) had similar incidence of AEs: infections and infestations (23.0% and 24. 0%), followed by skin / subcutaneous tissue disorders (17.5% and 16.9%) (Table 5). The incidence of AEs reported in ES and CS was similar, with headache (6.6% and 9. The most common adverse events were infection (23%), bleeding (4.4%) and cytopenia (0. The incidence of AESI in ES was consistent with CS, with 5% of patients with AESI occurring after surgery. Increased transaminases were associated with ES (isolated ALT > 3xULN, normalizing within 4 weeks) , early discontinuation for personal reasons in one patient) and CS (ALT > 5x in one patient). The analysis of laboratory parameters revealed that only one of the following was positive for either ULN or normalized with treatment: No significant safety concerns were identified, and no clinically meaningful changes in vital signs were observed. No significant ECG findings or QT >500 ms were observed in any patient. It was not allowed.

[0253] conclusion Remibrutinib demonstrated a favorable safety profile across the entire dose range and was associated with improved CSU New evidence suggests that the effect of prolonged exposure to a 100 mg bid dose for up to 52 wks in patients No significant safety signals were observed.

[0254] [Table 7]

[0255] Example 5 Below, a preferred pharmaceutical composition (film-coated tablet) is described.

[0256] [Table 8]

[0257] Example 6 Below, another preferred pharmaceutical composition (hard gelatin capsule) is described.

[0258] [Table 9]

[0259] [Table 10]

[0260] The hard gelatin capsules have demonstrated good stability with a current shelf life of 36 months.

[0261] Example 7 Prediction of BTK occupancy using a translational PK / PD model of LOU064 BTK occupancy in blood is controlled by the pharmacological properties of LOU064 (irreversible binding). Not a useful biomarker for dose selection purposes. Other biomarkers (CD63, CD2 03c, skin prick test) demonstrates full occupancy at low doses before demonstrating pharmacological activity The tissue occupancy rate can better represent the efficacy of LOU064.

[0262] the purpose The objective of this analysis was to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers. Using previously developed translational target occupancy models, BTK occupancy in human spleen / tissues across ranges and dosing regimens (BID vs. QD) It was to simulate.

[0263] data In this study including 102 patients, the results reported by Kaul et al. Pharmacokinetic data from the previously reported Phase I clinical study were used.

[0264] method To simulate BTK occupancy in spleen / tissues using a two-step approach We developed a translational target occupancy model for .

[0265] In the first phase, a phase I clinical study reported by Kaul et al. (2021) A population PK model was established to describe the PK data of LOU064. Using parameter estimates from the population PK model in the BTK occupancy model, We predicted BTK occupancy in spleen / tissues. Finally, we used the BTK occupancy model to , BTK in spleen / tissues for different dosing regimens (QD, BID) at different doses The occupancy rate was predicted.

[0266] result Interim PK from a Phase I clinical study reported by Kaul et al. (2021) A population PK model was developed to describe the pharmacokinetic profile of Change in clearance after administration of 100 mg / kg / day (clearance was 100% at steady state on day 12 compared to day 1) For doses below 50 mg, there was no difference between the lower and higher doses. As a function of exponential decay over time, the clearance appears to be constant at doses above 50 mg. Overall, the resulting population model adequately supported the PK data. It was written in a reasonable amount of detail.

[0267] PK parameter estimates were used in a translational BTK occupancy model to determine steady-state We simulated the BTK occupancy in the β-terminal state. To achieve high BTK occupancy (trough or average over a 24-hour interval), demonstrated that BID administration was more effective than QD administration.

[0268] For selected doses in QD and BID regimens, The rough and average steady-state BTK occupancy is shown in Figure 21A (24-hour change in steady-state BTK occupancy). 21B (Trough over 24 hours) and FIG. 21B (Average BTK occupancy at steady state over 24 hours) These are shown in Table 1, which are 10 mg, 35 mg, 100 mg, and twice daily, respectively. For the 10 mg, 25 mg and 100 mg dosage regimens. Up to 200m to achieve ≥80% trough BTK occupancy in peripheral target tissues g (100 mg BID) may be required.

[0269] Simulations were performed to compare different dosing regimens. Comparison of simulated steady-state splenic BTK occupancy over time for 100mg QD vs. 100mg QD The results are shown in Figure 22. The graph shows that the occupancy rate from BID administration is higher compared to QD. This indicates that the value does not fluctuate much.

[0270] Conclusion: Simulations of BTK occupancy are performed with a higher BTK occupancy rate (a 24-hour interval BID administration is more effective than QD administration at the same dose to achieve a rough or average It was shown that.

[0271] Example 8 Phase III Clinical Study Demonstrating Efficacy and Safety of LOU064 in Treating Patients with RMS the purpose The frequency of confirmed relapses, as assessed by the annualized relapse rate (ARR), in subjects with relapsing MS. LOU064 (100 mg orally bid) was shown to reduce teriflunomide ( 14 mg orally once daily) in patients with multiple sclerosis Treat with LOU064.

[0272] method In the treatment of patients with RMS and in its long-term open-label safety extension study, g bid) versus teriflunomide (14 mg), A double-blind, randomized, double-dummy, active comparator study of In total, approximately 1,600 subjects (800 per study) will participate in these Phase III studies.

[0273] Patients were randomized (1:1) to receive LOU064 starting on Day 1 for up to 30 months. 00 mg orally bid or teriflunomide 14 mg orally once daily The duration of the study is flexible and will be pre-specified during the blinded core treatment phase. The disease is terminated according to the 2017 McDonald diagnostic criteria (which includes relapsing-remitting The course of MS may include secondary progressive MS (RRMS) or secondary progressive MS (SPMS) course. Patients aged 18-55 years who have been diagnosed with relapsing MS and have a mean score of 0-5.5 at screening Expanded Disability Status Scale (EDSS) score of Kurtzke, Neurology: 198 3,Nov;33(11):1444-52) and have had at least one relapse in the past year or ≥2 recurrences in the past 2 years, or a positive gadolinium test in the 6 months prior to randomization Patients must have had a Gd-enhanced MRI scan and have had a neurological history of 1 month prior to randomization. Stable patients were included.

[0274] The primary endpoint of the study was the annualized relapse rate (ARR), or confirmed relapses per year. Key secondary outcomes included disability endpoints (pooled CD P, i.e., 3-month persistence on EDSS based on pooled data from 2 studies Disability, as measured by disability progression (3mCDP) and 6-month sustained progression (6mCDP) time to progression), MRI endpoints (i.e., T1 gas per MRI scan), Number of Gd-enhancing lesions, new T2 lesions or enlargement on MRI per year number of T2 lesions (annualized T2 lesion rate), serum neurofilament light chain (N fL) concentrations, and no evidence of disease activity-3 based on pooled data from two studies and (NEDA3), as well as brain volume loss based on assessment of percent brain volume change from baseline. (BVL) percentage is included.

[0275] ARR and MRI endpoints were analyzed using the NB model; CDP endpoints The data are analyzed using Cox regression models.

[0276] A total of approximately 800 subjects were randomized to each study in a 1:1 ratio (400 per treatment group) The randomized control group was randomized to 100 mg / kg / day, and the mean mean age of 100 mg / kg / day was 15.6 months. 64) assuming a 40% relative reduction in ARR and a 2-year dropout rate of 20%. The primary endpoints of each study (ARR) were compared for superiority of LOU064 over teriflunomide. Provides over 90% power to demonstrate positional efficacy. Combined, 1600 participants from two studies Patients with 40% risk reduction based on a one-sided test at the 0.025 significance level and 2-year dosing Assuming a dropout rate of 20%, the effect of LOU064 on teriflunomide in 3mCDP was In addition, it provides 90% of the power to demonstrate superiority over other anti-RMS drugs in the treatment of patients with RMS. LOU064 (100 mg bid) compared with teriflunomide (14 mg QD) The efficacy and superiority of LOU064 treatment were confirmed by side effects such as SDMT, T25FW and 9HPT. By measuring secondary outcomes, as well as the MSIS-29, HUI-III, and PHQ Patient-reported outcomes were measured using the ANOVA-9, GAD-7, FSIQ-RMS and BPI-SF. It is also evaluated by

[0277] A summary of the secondary outcome measures is presented in the following table:

[0278] [Table 11]

[0279] [Table 12]

[0280] To determine the long-term safety and efficacy of LOU064 (100 mg bid), Do the long part.

[0281] The extension part is an open-label, single-arm, fixed-dose design and eligible participants will be randomized to receive the study for up to 5 years. Participants who received LOU064 in the core study (up to 30 months) Continue LOU064 (100 mg bid) and teriflunomide (14 mg bid) in the core study. Participants who received LOU064 (100 mg bid) will be switched to LOU064 (100 mg bid).

[0282] [Table 13]

[0283] [Table 14]

[0284] Example 9 scRNA-seq analysis of rat MOG EAE mice treated with LOU064 method Processing and quality control of scRNA-seq data 10X Genomics Chromium raw sequence read data was processed by Cell R anger [Zheng, G. et al. (2017), Nat Co All subsequent analyses were performed using the Orchestrating Systems Single-cell analysis with Bioconductor IDLINE [Amezquita, RA et al (2020), Nat Meth ods 17, 137-145], scuttle, scater [Da vis J McCarthy et al.(2017),Bioinformati cs, Vol 33, 8, 1179-1186] and scran [Lun ATL et al.(2016),F1000 Research,5:2122;https: / / doi.org / 10.12688 / f1000research.9501.2] Using the framework provided by the package, R v4.1 and Biocondu The samples were run using ctor v3.14. One sample had a low number of UMIs per cell. This was excluded from the analysis due to suspected contamination with surrounding RNA. This is due to the small library size, low number of detected genes, or mitochondrial reads. Low-quality cells with high chromatin density were removed. Doublets were identified using scDblFinder. , removed [Germain PL et al. (2021) F1000 Research ch 10:979;https: / / doi.org / 10.12688 / f1000 In total, 76,287 cells passed quality control. Ta.

[0285] Regularization, feature selection and dimensionality reduction To correct for library size and composition bias, cells were pooled and a size factor was calculated. After convolution, normalization was performed by log2 transformation. The mean-variance relationship of each gene was modeled separately for the two tissues. Using a 5% FDR threshold under the null hypothesis that the elements are equal to zero, we identified highly variable genes These genes were then used to perform principal component analysis to determine the biological role of gene mutations. Only PCs that are relevant to the element were kept. Finally, the selected PCs were used to determine the dimensionality of the data. A reduced representation was obtained (UMAP).

[0286] Clustering and cell type annotation Five nearest neighbors, Jaccard coefficient as a weighting scheme, and clustering methods We use the shared nearest neighbor graph-based clustering approach by Louvain as the Using SingleR [Aran D et al. (2019), Nat Immunol. 20, 163-172] and two sets of mice Bulk transcriptomics references for cell types [Heng TS et al. (2008), Nat. Immunol. 9, 1091-1094; Benayoun b et al.(2019),Genone Res.29,697-709] We used the UCell [Andreatta M. et al.(2021),Comput Struct Biotechnol J.19 :3796-3798] and marker genes [Deczkowska A et al. (2018), Cell.17;173(5):1073-1081] and Microglia are further divided into homeostatic microglia (HM) and disease-associated microglia (DAM). and annotated.

[0287] Differential expression and enrichment analysis For each cell type, edgeR [Robinson MD et al. (2010) ,Bioinformatics,26(1),139-140] to perform pseudo bulk difference After performing secondary expression analysis, fgsea [Gennady Korotkevich t al.,doi:https: / / doi.org / 10.1101 / 060012 ] and gene set enrichment analysis using MSigDB [Arthur Lib erson et al.,Bioinformatics,Vol 27,12:17 We performed a multi-gene set collection from [Human Phe notype Ontolog[Koehler S.et al.(2021)Nuc leic Acids Res.49(D1):D1207-D1217.doi:10 .1093 / nar / gkaa1043] to UCell [An dreatta M.et al.(2021),Comput Struct Bio Technol J.19:3796-3798] and the significance was assessed one-sidedly. Evaluated by Mann-Whitney U test.

[0288] result Inhibition of Btk in rat MOG EAE mice by LOU064 resulted in increased expression of Btk in microglial cells. Attenuating neuroinflammation in Using scRNA-seq, we identified 100% methylglutamine (MG) in rats treated with LOU064 or normal diet. By profiling the brain and spinal cord of EAE mice, we were able to identify interstitial cells (fibroblasts, endothelial cells), all major immune cell types recruited to the CNS (B cells, T cells, DCs, monocytes and macrophages), as well as the resident cells of the CNS: neurons, neuroepithelial cells, astrocytes, and Cytoplasmic cells, oligodendrocytes, and microglia (further classified into HM and DAM) Thirteen different cell types were identified, including

[0289] Differentially expressed genes between LOU064-treated animals and controls across 13 cell types Following identification of the offspring, a neuroinflammatory gene signature (Human Phenotype On To determine whether LOU064 is responsible for the expression of IL-1 in microglia, we investigated whether the expression of IL-1 in microglia is influenced by LOU064. We investigated whether IFN-γ-γ was downregulated in 1H-terminal β-lactamase and observed significant downregulation across most conditions (Figure 23).

[0290] Example 10: Three different patterns of remibrutinib administration and withdrawal in healthy subjects Evaluation of modulation of immune responses to vaccines of various types

[0291] [Table 15]

[0292] research design Overall design This randomized, double-blind, placebo-controlled study had a parallel-group design. Considering the drop-out rate, approximately 90 people will be required to achieve a minimum of 72 assessable completers. Healthy non-childbearing female and male participants were randomized to one of three treatment groups. The study consisted of a 28-day screening period, a 43-day treatment period, followed by a final This will consist of a study completion evaluation (Day 57) within 2 weeks of dosing. A safety follow-up call will be conducted approximately 30 days later (Day 73). Participants were housed on days 1 through 17 and days 14 through 17. Overall, the maximum study duration for each participant was 85 days. Between.

[0293] Influenza / Pneumovax® 23 and Immucothel The impact of concomitant and interrupted remibrutinib treatment scenarios for the treatment of patients with refractory rheumatoid arthritis (RR) on placebo and evaluate.

[0294] Conducting the research Screening & Baseline Participants who meet the eligibility criteria at screening will enter a baseline assessment on Day -1. All baseline safety assessments must be available prior to the first dose. At baseline, participants were randomized to one of three treatment arms: will be done.

[0295] treatment All participants received either remibrutinib 100 mg or placebo from Day 1 to Day 42. All patients received 10 mg / kg bid and returned to the clinic for their end of treatment visit on day 43. Participants were administered the quadrivalent influenza vaccine, PPV-23 vaccine, and KLH on day 15. You will also receive a neoantigen vaccine. Vaccination should be administered 3 hours after administration of the investigational drug. be.

[0296] During the clinical visits and residency (days -1 to 1 and 14 to 17), participants Patients will be administered the study drug by the study staff at the clinic. Along with the journal, participants will be provided with the study medication to self-administer at home.

[0297] Safety assessments included physical examination, ECG, vital signs, and standard clinical laboratory evaluations (blood Clinical trials may include clinical evaluations (e.g., clinical chemistry, blood chemistry, urinalysis) and monitoring for adverse events and serious adverse events.

[0298] To evaluate the pharmacokinetics of remibrutinib, all Multiple blood samples may be taken from the participant.

[0299] Group A (combination treatment with remibrutinib): Participants received a placebo (bid) on days 1-7, then received one of the three vaccines on day 15. Prior to dosing with rivaroxaban, remdesivir should be administered on days 8-15 of the study to achieve PK / PD steady state. Participants will receive treatment with tinib (100 mg bid). Administration of remibrutinib (100 mg bid) may be continued until

[0300] Group B (discontinuation of remibrutinib treatment): Participants were randomized to receive 100 mg of remibrutinib on days 1-7 to achieve PK / PD steady-state conditions. Treatment with 0 mg bid followed by placebo (bid) on days 8-28 The patient will receive 100 mg of remibrutinib and 3 vaccines on the 15th day. Bid treatment may be resumed on days 29 to 42.

[0301] Group C (placebo): Participants in group C received placebo (bid) on days 1–42 and placebo on day 15. Under certain conditions, the animals will be vaccinated with three vaccines.

[0302] Key inclusion criteria Signed informed consent must be obtained before participating in the study . 18–55 years of age (inclusive) who are in good health or who are mildly obese but otherwise in good health Healthy male and non-childbearing female participants. Participants will complete a medical history, physical examination, and In good health as determined by vital signs, ECG, and clinical examination It must be. At screening and baseline, vital signs (systolic and diastolic blood pressure, Patients' blood pressure and pulse rate are assessed in the sitting position and again (if required by the assessment schedule) in the standing position. Sitting vital signs (after 3 minutes of sitting) should be within the following ranges: do not have: · Eardrum temperature 35.0~37.5℃. Systolic blood pressure (SBP) 90 and 139mmHg (inclusive). Diastolic blood pressure (DBP) 50 and 89mmHg (inclusive). Pulse rate 45 and 90 bpm (inclusive). Participants must weigh at least 50kg to participate in the study and They must have a body mass index (BMI) in the range of 8 to 34.9 kg / m2. Participants remain at the clinical site as required by the protocol and follow the procedures outlined in the ICF. Must be willing to comply with any requirements / instructions given to them. Able to read, speak and understand the local language to understand and comply with the requirements of this study. can.

[0303] Key Exclusion Criteria 1. Use of other investigational drugs within 5 half-lives or 30 days prior to the first dose, whichever is longer. For. 2. Current evidence or history of clinically significant ECG abnormalities or long QT syndrome or or family history of other cardiac conduction abnormalities (grandparents, parents, and siblings), polymorphic ventricular tachycardia (T History and / or known additional risk factors for dP (e.g., heart failure, hypokalemia) History or current clinically significant arrhythmia. Abnormal ECG: PR>220 msec, QR S complex > 120 msec, QTcF > 450 msec in both sexes, or any other condition other than early repolarization This is defined as any other morphologic change of interest, nonspecific ST or T wave changes. 3. Any treated or untreated disease within the past 5 years, with or without evidence of local recurrence or metastasis History or presence of organ system malignancy (other than localized basal cell carcinoma of the skin or cervical intraepithelial neoplasia) . 4. Cardiovascular, pulmonary, metabolic, hepatic, renal, or hematological disorders that were not resolved within 2 weeks prior to the initial dose Any major organ system class, including but not limited to, endocrine, neurological or psychiatric disorders History or presence of clinically significant disease. 5. Hypersensitivity to remibrutinib or to drugs from the same compound class or its excipients. 6. Acute infection, fever or hypersensitivity reaction, or any related reaction to the vaccine administered in this study. Pneumov, including known hypersensitivity to related ingredients (e.g., chicken eggs or shellfish / KLH) ax 23, contraindication to use of influenza or KLH vaccines. 7. Vaccination history or registration for 2022-2023 seasonal influenza vaccine Known clinical cases of influenza infection during the previous 2022-2023 influenza season diagnosis. 8. History of previous exposure or immunization with KLH.

Claims

1. LOU064, or a pharma- ceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

2. Claims wherein LOU064 is administered orally twice daily at a dose of about 50 mg to about 150 mg.

1. LOU064 for use as described in

3. 3. The method according to claim 1 or 2, wherein LOU064 is orally administered twice daily at a dose of about 100 mg. LOU064 for use as described above.

4. LO for use according to any one of claims 1 to 3, wherein the treatment is a chronic treatment. U064.

5. The multiple sclerosis is relapsing multiple sclerosis, in particular clinically isolated syndrome (CIS); Relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), especially L for use according to any one of claims 1 to 4 is selected from among highly active SPMS. OU064.

6. Claims 1 to 5, wherein the patient is switched from a previous disease modifying therapy drug to LOU064.

2. The method of claim 1, wherein the medicament is a medicament for use in a medical device.

7. The prior disease modifying therapy drug is a B-cell and / or T-cell inhibitor, teriflunomide, Mitoxantrone, dimethyl fumarate, cladribine, fingolimod, siponimod, Nesimod, glatiramer acetate, and interferons (e.g., beta interferon 7. The method of claim 6, wherein LOU064 is selected from the group consisting of

8. 8. The method of claim 6 or 7, wherein the previous disease modifying therapy lacks efficacy. LOU064.

9. Any of claims 6 to 8, wherein the patient has a lack of tolerance to the previous disease modifying therapy. LOU064 for use according to any one of the preceding claims.

10. The method of claim 6 to 9, wherein the previous disease-modifying therapy is discontinued before starting administration of LOU064. LOU064 for the use according to any one of the claims.

11. LOU064 was selected if the patient was planning to become pregnant within the next 12 months.

11. The method of claim 1, further comprising administering to said patient a therapeutically effective amount of LOU064.

12. If the patient plans to receive chemotherapy within the next 12 months, LOU064 Selected LOU064 for use according to any one of claims 1 to 11.

13. LO for use according to any one of claims 1 to 12, wherein the treatment is a monotherapy. U064.

14. The method according to any one of claims 1 to 13, wherein LOU064 is not administered in combination with a strong inhibitor of CYP3A. LOU064 for the use according to any one of the claims.

15. Claims 1 to 14, wherein LOU064 is not administered in combination with a strong inducer of CYP3A4.

2. The method of claim 1, wherein the medicament is a medicament for use in a medical device.

16. The method of claim 1, wherein a patient acutely or previously infected with COVID-19 is treated.

15. LOU064 for use according to any one of claims 15.

17. The method according to any one of claims 1 to 16, wherein the treatment is continued during COVID-19 infection. LOU064 for use as described above.

18. The treatment is interrupted during COVID-19 infection and continued after overcoming the infection. LOU064 for use according to any one of claims 1 to 16.

19. The method according to any one of claims 1 to 18, wherein the treatment is an ethnicity-neutral treatment. For use LOU064.

20. The use according to any one of claims 1 to 19, wherein LOU064 is administered after relapse. For LOU064.

21. 20. The method of claim 1, wherein LOU064 is administered after detection of at least one Gd+ lesion.

2. The method of claim 1, wherein the medicament is a medicament for use in a medical device.

22. LOU064 is administered following detection of a new or enlarging T2 lesion.

22. LOU064 for use according to any one of claims 1 to 21.

23. The LOU0 for use according to any one of claims 1 to 22, wherein the patient is an adult. ６４。

24. The patient undergoes treatment for up to 24 months, preferably 12 to 24 months, of the following: - Compared to untreated patients and / or to interferon, teriflunomide, glucagon acetate Latiramer and dimethyl fumarate, preferably interferon, teriflunomide and More preferably, it is selected from dimethyl fumarate, teriflunomide or interferon. Reduction in the mean total number of gadolinium-enhancing lesions compared with patients receiving alternative disease-modifying treatments Few, - Compared to untreated patients and / or to interferon, teriflunomide, glucagon acetate Latiramer and dimethyl fumarate, preferably interferon, teriflunomide and More preferably, it is selected from dimethyl fumarate, teriflunomide or interferon. Reduced annualized relapse rate compared with patients receiving alternative disease-modifying treatments, - Interferon, teriflunomide, glatiramer acetate and dimethyl fumarate, preferred Preferably, interferon, teriflunomide and dimethyl fumarate, more preferably Patients receiving another disease-modifying therapy selected from teriflunomide or interferon longer time to achieve 3-month sustained disability progression compared with For the use according to any one of claims 1 to 23, LOU064.

25. Alanine aminotransferase ( ALT), aspartate aminotransferase (AST), and lipase levels does not change by more than 10% by 12 or 24 weeks of treatment.

2. The method of claim 1, wherein the medicament is a medicament for use in a medical device.

26. The treatment is effective in reducing annual relapse rates at least as effectively as CD20 depletion therapy.

26. The method of claim 1, wherein the compound is an active ingredient in the composition of the present invention.

27. The patient is vaccinated during LOU064 therapy, in particular with a non-live vaccine.

27. The method of claim 1, further comprising administering to said patient a therapeutically effective amount of LOU064.

28. LOU064 is administered in the form of a suitable oral pharmaceutical formulation containing nano-sized particles of LOU064.

28. The method of claim 1, further comprising administering to said patient a therapeutically effective amount of LOU064 for use according to any one of claims 1 to 27.

29. LOU064 has an average particle size between about 50 nm and about 750 nm as measured by PCS. The compound is administered in the form of a suitable oral pharmaceutical formulation comprising nano-sized particles of LOU064 having the claimed compound.

29. LOU064 for use according to any one of claims 1 to 28.

30. LOU064 is a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 2:

1. LOU06 for use according to any one of claims 1 to 29, administered in the form of a drug ４。

31. LOU064 is a mixture of LOU064, a binder, and a surfactant in a weight ratio of about 2:1:0.

08. The composition according to any one of claims 1 to 30, which is administered in the form of a suitable oral pharmaceutical formulation comprising For use LOU064.

32. LOU064 is a suitable oral pharmaceutical preparation comprising LOU064 and a binder in a weight ratio of about 1:

1. LOU06 for use according to any one of claims 1 to 29, administered in the form of a drug ４。

33. LOU064 is a mixture of LOU064, a binder, and a surfactant in a weight ratio of about 1:1:0.

05.

33. The composition according to claim 1, wherein the composition is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 for use as described in

34. LOU064 is a polyvinylpyrrolidone-vinyl acetate copolymer as a binder. of a suitable oral pharmaceutical formulation comprising a polymer and sodium lauryl sulfate as a surfactant.

34. The method of claim 1, wherein LOU064 is administered in the form of a pharmaceutical preparation.

35. 35. The method of claim 1, wherein LOU064 is co-administered with an oral contraceptive. For use LOU064.

36. LOU064 for the manufacture of a medicament for use in the treatment of multiple sclerosis. Preferably, the agent is administered orally twice daily at a dose of about 50 mg to about 150 mg. , LOU064.

37. A method of treating or preventing multiple sclerosis, comprising administering to a patient in need of such treatment. administering to said patient a therapeutically effective oral dose of LOU064.

38. 38. The method of claim 37, wherein the therapeutically effective dose is about 50 mg to about 150 mg twice daily. The method described.

39. The multiple sclerosis is relapsing multiple sclerosis, in particular clinically isolated syndrome (CIS); Relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), especially 39. The method of claim 37 or 38, wherein the symptom is selected from actively active SPMS.

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