Methods and compositions for treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus

Abstract

The present invention provides compositions and methods for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus or systemic lupus erythematosus. In one embodiment, the invention provides a method or a compound for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus or systemic lupus erythematosus in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a Compound 1, (I) or a pharmaceutically acceptable salt thereof.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING DISCOID LUPUS ERYTHEMATOSUS, SYSTEMIC LUPUS ERYTHEMATOSUS, AND SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 543,357, filed on October 10, 2023 and U.S. Provisional Application No. 63 / 631,730, filed on April 9, 2024. The entire teachings of the above applications are incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] Discoid lupus erythematosus and subacute cutaneous lupus erythematosus are characterized by formation of lesions on the face and scalp. Discoid lupus erythematosus involves the formation of circular skin lesions. Treatment is often based on administration of steroids, e.g., injection or topical application of corticosteroids. Anti-inflammatory drugs such as dapsone or low-dose methotrexate can reduce pain and swelling.

[0006] Systemic lupus erythematosus (SLE) is an indication wherein the immune system attacks multiple organs with a wide variety of adverse effects depending upon the organs involved. Generally, 70 to 85% of SLE patients display some level of cutaneous manifestations with an appearance similar to the lesions associated with discoid lupus erythematosus and subacute cutaneous lupus erythematosus. Up to 25% of SLE patients have cutaneous symptoms as the initial presenting symptom of the disease. (Yell, J. A. et al. British Journal of Dermatology 1996, 135:355-362; Shi, H., et al., Curr Opin Rheumatol 2020, 32:208-214). Tukaj et al. Cell Stress and Chaperones (2019) 24:475-479 and Tukaj et al. Biomolecules (2022) 12, 1153 review heat shock proteins as potential treatment targets in the therapy of autoimmune diseases.

[0007] The role of HPS90 inhibitors has been investigated by Liu et al. (The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRI / lpr Mouse Model of Systemic Lupus Erythematosus, PLOS ONE | DOI: 10.1371 / joumal. pone.0127361, 14 May 2015) in systemic lupus erythematosus (SLE), which is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations.

[0008] There remains, however, a need for new compositions and methods for treating discoid lupus erythematosus and subacute cutaneous lupus erythematosus. SUMMARY OF THE INVENTION

[0009] The present invention provides compositions and methods for treating discoid lupus erythematosus and subacute cutaneous lupus erythematosus. In one embodiment, the invention provides a method for treating discoid lupus erythematosus, systemic lupus erythematosus or subacute cutaneous lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0010] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating discoid lupus erythematosus, systemic lupus erythematosus or subacute cutaneous lupus erythematosus.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 presents graphs of IL1B qPCR data in non-lesional and lesional skin biopsies treated from three discoid lupus erythematosus patients following in vitro treatment with DMSO vehicle or Compound 1.

[0013] Figure 2 presents graphs of IFNy qPCR data in non-lesional and lesional skin biopsies treated from three discoid lupus erythematosus patients following in vitro treatment with DMSO vehicle or Compound 1.

[0014] Figure 3 presents graphs of CXCL10 qPCR data in non-lesional and lesional skin biopsies treated from three discoid lupus erythematosus patients following in vitro treatment with DMSO vehicle or Compound 1. Figure 4 presents graphs of IL6 qPCR data in non-lesional and lesional skin biopsies treated from three discoid lupus erythematosus patients following in vitro treatment with DMSO vehicle or Compound 1.

[0015] Figure 5 presents graphs of IL18 qPCR data in non-lesional and lesional skin biopsies treated from three discoid lupus erythematosus patients following in vitro treatment with DMSO vehicle or Compound 1.

[0016] Figure 6 is a graph showing the concentrations of Compound 1 found in biopsied tissues in subjects as described in the Example 2.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention relates to methods and a compound for treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus. In one embodiment, the invention provides a method of treating systemic lupus erythematosus, discoid lupus erythematosus and subacute cutaneous lupus erythematosus in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus.

[0019] Compound 1 is a potent inhibitor of HSP90, and the synthesis and HSP90 inhibitory activity of Compound 1 are described in W02008 / 115719, the contents of which are incorporated by reference herein in their entirety.

[0020] In the methods and compounds for treating systemic lupus erythematosus, discoid lupus erythematosus and subacute cutaneous lupus erythematosus of the invention, the subject is preferably a human subject. The subject can have systemic lupus erythematosus, discoid lupus erythematosus and / or subacute cutaneous lupus erythematosus with symptoms at any degree of severity. For example, the subject can have systemic lupus erythematosus with cutaneous manifestations, diffuse discoid lupus erythematosus or subacute cutaneous lupus erythematosus.

[0021] In certain embodiments, the subject suffers from systemic lupus erythematosus with cutaneous manifestations, such as cutaneous lesions, and Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount which is effective to diminish or alleviate the cutaneous manifestations. In certain embodiments the systemic lupus erythematosus is bullous systemic lupus erythematosus. Compound 1 or a pharmaceutically acceptable salt thereof is preferably administered in the form of a pharmaceutical composition comprising the therapeutic agent and a pharmaceutically acceptable carrier, excipient or diluent. Suitable pharmaceutical compositions include a solid, semisolid or liquid preparation (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection, etc.). The pharmaceutical composition can be administered by any suitable means, including, without limitation, parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal administrations or the like. Topical administration can involve the use of transdermal administration such as transdermal patches or iontophoresis devices.

[0022] In a preferred embodiment, the pharmaceutical composition is administered orally, for example, as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. In another embodiment, the composition is formulated as a tablet. The Compound 1 shows unexpectedly high accumulation in the skin following oral dosing.

[0023] Any inert excipient that is commonly used as a carrier or diluent may be used in the pharmaceutical compositions of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof. Furthermore, the compositions of the present invention may be in the form of controlled release or immediate release formulations.

[0024] For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. Solutions or suspensions can also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0025] In addition, the compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol, polyethylene glycol), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., pol oxamers or pol oxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.

[0026] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0027] It is especially advantageous to formulate oral compositions in unit dosage form for ease of administration and uniformity of dosage. “Unit dosage form”, as used herein, refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0028] Formulations of the invention intended for oral administration can include one or more permeation enhancers, including long chain fatty acids or salts thereof, such as decanoic acid and sodium decanoate.

[0029] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0030] The pharmaceutical composition of the invention is preferably suitable for oral administration, such as a tablet or a capsule, and is most preferably in the form of a tablet. In one embodiment, the pharmaceutical composition is a tablet comprising Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments the tablet comprises Compound 1 in the form of the free base. In certain embodiments, the tablet comprises Compound 1 free base in an amount from 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg. Alternatively, the tablet comprises a pharmaceutically acceptable salt of Compound 1 in the foregoing amounts where these amounts represent free base equivalents. Preferably, the tablet comprises 0.5 mg, 1 mg, 5 mg, 20 mg, 50mg, 100 mg, 125 mg or 250 mg of Compound 1 free base.

[0031] In certain embodiments, the pharmaceutical composition of the invention is suitable for topical administration and is most preferably in the form of a cream, a lotion, a gel, an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices. In one embodiment, the pharmaceutical composition is a cream comprising Compound 1. In certain embodiments, the cream comprises Compound 1 in the form of the free base. In certain embodiments, the cream comprises Compound 1 free base in an amount from 0.25 mg to 250 mg, from 0.5 mg to 225 mg, from 1 mg to 200 mg, from 1.5 mg to 175 mg, from 2 mg to 150 mg, from 2.5 mg to 125 mg, from 3 mg to 100 mg, from 4 mg to 75 mg, from 4.5 mg to 50 mg, from 5 mg to about 25mg. Preferably, the cream comprises 0.5 mg, 1 mg, 5 mg, 20 mg, 50 mg, 100 mg, 125 mg or 250 mg of Compound 1 free base. Alternatively, the cream comprises a pharmaceutically acceptable salt of Compound 1 in the foregoing amounts where these amounts represent free base equivalents.

[0032] The pharmaceutical composition can be administered daily or on a suitable schedule. In one embodiment, daily administration is repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. The administration can be continuous or intermittent, e.g., treatment for a number of consecutive days followed by a rest period.

[0033] The amount of the compound administered to the patient is preferably less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the Compound 1 or pharmaceutically acceptable salt thereof that is administered to the patient is less than the amount that causes a concentration of the Compound In the patient's plasma to equal or exceed the toxic level of the compound.

[0034] The dosing schedules described herein describe administration of Compound 1, which can be administered in the form of the free base or as a pharmaceutically acceptable salt. Any amount of Compound 1 administered in the dosing regimens described herein refers to the amount of the free base form. The dosing regimens disclosed herein include administration of a pharmaceutically acceptable salt of Compound 1, in which embodiments the doses disclosed herein refer to free base equivalent amounts.

[0035] In certain embodiments, Compound 1 is administered at a dose of 0.5 mg to 400 mg per dosing day. In certain embodiments, Compound 1 is administered at a dose of 10 mg to 50, 100 or 200 mg per dosing day. In certain embodiments, Compound 1 is administered orally to the subject at a dose of 0.5 mg to 300 mg per dosing day, 25 mg to 275 mg per dosing day, 30 mg to 260 mg per dosing day or 250 mg per dosing day. In certain embodiments, Compound 1 is administered orally to the subject at a dose of 0.5 mg to 200 mg per dosing day, 20 mg to 175 mg per day, 20 mg to 150 mg per dosing day, 20 mg to 125 mg per dosing day, 20 mg to 100 mg per dosing day, or 20 mg to 50 mg per dosing day. In certain embodiments, Compound 1 is administered orally to the subject at a dose of 50 mg to 150 mg per dosing day, 60 mg to 140 mg per dosing day, 70 mg 130 mg per dosing day, 75 mg to 125 mg per dosing day, 80 mg to 120 mg per dosing day, 90 mg to 110 mg per dosing day or 100 mg per dosing day.

[0036] In certain embodiments, Compound 1 is administered orally to the subject at a dose of 150 mg to 300 mg per dosing day, 200 mg to 300 mg per dosing day, 225 mg to 275 mg per dosing day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per dosing day.

[0037] The term “dosing day”, as used herein, refers to a day on which Compound 1, in the form of the free base or a pharmaceutically acceptable salt, is administered to the subject. In certain embodiments, Compound 1 is administered to the subject daily. In other embodiments, Compound 1 is administered every other day. In certain embodiments, Compound 1 is administered to the subject three days per week, preferably on non- consecutive days, for example on Monday, Wednesday and Friday. The dose mentioned is the amount of drug per day and will correlate to the concentration of drug in the specific dosage format and the amount / area applied.

[0038] In certain embodiments, Compound 1 is initially administered to the subject at a loading dose of 0.5-250 mg per dosing day for a suitable period of time, such as 1-12 weeks, 2-10 weeks or 4 to 8 weeks. The loading dose is preferably administered daily. The loading dose can be followed by a reduced maintenance dose, for example any of the reduced dosing schedules and / or reduced doses per dosing day as described above. For example, Compound 1 can be administered at loading dose of 25-250 mg / dosing day for 4 to 8 weeks, followed by a maintenance dose of 0.5-200 mg per dosing day, provided that the maintenance dose is a lower dose per dosing day and / or dosed less frequently than the loading dose. In certain embodiments, the loading dose is 200 to 250 mg per day for 4 to 8 weeks and the maintenance dose is 25 to 200 mg per day, provided that the maintenance dose is lower than the loading dose.

[0039] Dosing of Compound 1 or a pharmaceutically acceptable salt thereof as described above can continue for any period of time and is preferably continued for at least 16 weeks or more. Preferably dosing continues as long as the subject is exhibiting clinical improvement in the signs and symptoms of discoid lupus erythematosus and subacute cutaneous lupus erythematosus.

[0040] Dosing of Compound 1 or a pharmaceutically acceptable salt thereof as described above can be interrupted by occasional periods of one or more days in which dosing is suspended, and then dosing can be continued either on a predetermined scheduled or upon return or worsening of discoid lupus erythematosus and subacute cutaneous lupus erythematosus signs and symptoms. Response of a subject to the therapeutic methods of the present invention can be determined as is known in the art. For example, the subject can be evaluated according to the Physician’s Global Assessment (PGA) and / or Dermatology Life Quality Index (DLQI).

[0041] DEFINITIONS

[0042] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0043] Compound 1 can be formulated and administered in the methods of the invention as the free base or as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0044] As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.

[0045] The term “subject” as used herein refers to an animal. Preferably the animal is a mammal. Most preferably, the subject is a human.

[0046] The terms “therapeutically effective amount" and “effective amount” of a therapeutic agent refers to an amount of such agent which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to treatment of discoid lupus erythematosus, systemic lupus erythematosus or subacute cutaneous lupus erythematosus. A therapeutically effective amount of an agent may be different when used as a single agent than when used in combination with one or more other agents. In addition, a therapeutically effective amount of an agent may depend on the specific combination of agents to be administered. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). Therapeutically effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

[0047] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0048] Upon improvement of a patient’s condition, a maintenance dose of a compound or composition of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0049] Preparation of the compound of Compound 1

[0050] Compound 1 can be prepared using the methods disclosed in published PCT Application No. W02008 / 115719, the contents of which are incorporated herein by reference in their entirety.

[0051] Examples

[0052] Example 1 Effects of Compound 1 on Biopsied Skin of Discoid Lupus Patients

[0053] To investigate the effects of Compound 1 on inflammatory cytokines in the skin, 3 mm punch biopsies were taken from volunteer discoid lupus patients. Biopsies from each patient consisted of one taken from non-lesional skin and two from lesional skin areas. The biopsies were individually incubated in an apparatus to provide an air-liquid interface across each biopsy to mimic the skin orientation. The liquid used was a cell culture medium to which dimethylsulfoxide (DMSO, vehicle control) or Compound 1 (5 pM in DMSO) was added. Cultures were incubated for 24 hours before analysis to compare the relative gene expression. Reverse transcription was performed using TaqMan® Reverse Transcription Reagents (Applied Biosystems, Foster City, CA, USA). For qPCR, the mastermix used was Platinum® qPCR Super-mix-UDG (Invitrogen by Life Technologies). Primers / probes from Thermo Fisher Scientific against human: IFNgamma (Hs00989291_ml), IL-6 (Hs00174131_ml), IL-lbeta (HsOl 077958_sl), IL-18 (Hs01038788_ml), CXCL10 (Hs00171042_ml), IL-lbeta (Hs01555410_ml). As reference genes human RPLPO (assay ID: Hs99999902) (TaqMan Gene Expression assay, Thermo Fisher Scientific) were used for normalization. Each gene was analysed in triplets on the real-time qPCR machine Rotor-gene Q (Qiagen). The relative gene expression levels were determined from a standard curve for each gene made from a 4-fold serial dilution. As an internal reference, the consistently expressed human RPLPO gene was used to ensure experimental integrity and calibration.

[0054] The results of the study are presented in Figures 1-5. Figures 1-4 respectively show that lesional skin of each patient with Compound 1 results in decreased expression of IL1B, ZFNy, and CXCL10. Data consistently show that mRNA from these key cytokines known to be involved with the lupus-related autoimmune inflammation are all significantly reduced in lesional skin exposed to Compound 1. In contrast, Figure 5 shows no clear trend in expression of IL18 across the three patients demonstrating that Compound 1 does not inhibit an excessive number of biological pathways. Agents targeting single cytokine pathways have only exhibited limited clinical success. The complexity of lupus related autoimmune biological pathways suggests that down regulation of the multiple pathways induced by Compound 1 will result in greater efficacy.

[0055] Example 2 Pharmacokinetic Studies of Compound 1

[0056] A 16-week treatment, randomized, double-blind, proof-of-concept study was designed to assess the safety and efficacy of Compound 1 compared to placebo in treating hi dradenitis suppurativa. Eligible subjects completed an up-to 4-week screening phase and sequentially be randomized 2: 1 to one of two cohorts, treatment cohort (n = 10) or placebo-control cohort (n = 5), in a 16-week treatment phase followed by a 4-week observational follow-up phase. In the 16-week treatment phase, subjects randomized to the treatment group receive 250 mg Compound 1 free base in the form of a tablet administered orally once daily. The 250 mg dose was selected based on the results of an earlier oncology trial conducted with doses in excess of 1000 mg / day as a safe minimal dose from which to conduct dose escalation if required. Subjects randomized to the placebo-control group receive placebo treatment once daily (microcrystalline cellulose, mannitol, crospovidone, Opadry II red, magnesium stearate, colloidal silicon dioxide).

[0057] The accumulation of Compound 1 in the skin of human hi dradenitis suppurativa patients in the treatment cohort was determined. Snap frozen skin punch biopsies of non- lesional skin obtained at the week 16 visit showed high concentrations of Compound 1, indicating that Compound 1 accumulates in the skin. Figure 6 is a graph showing the concentrations of Compound 1 found in the biopsied tissues in subjects grouped according to their clinical response to Compound 1 therapy. The mean skin concentration following 16 weeks of treatment with Compound 1 was 7130 ng / mg, which is equivalent to 16.1 mM.

[0058] The skin accumulation found in this study was compared to plasma levels of Compound 1 determined in a previous study in healthy human volunteers. Six healthy male subjects were given a single oral dose of 250 mg Compound 1, and plasma samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 72 and 96 hours after dosing. The results of this study are shown in the table below.

[0059] The Cmax for Compound 1 determined for the six subjects ranged from 19.42 ng / mL to 24.92 ng / mL, with a median of 20.3 ng / mL or 46 nM.

[0060] The results show that the accumulation of Compound 1 is approximately 100,000- fold higher in the skin than in the plasma following daily oral dosing at 250 mg. In addition, the observed skin concentrations exceed the ICso of Compound 1 for inhibition of HSP-90 (0.1 pM) by a factor of about 104. One of skill in the art would understand that a daily oral dose of Compound 1 which is significantly less than 250 mg, for example, as low as 1 mg per day, will result in sufficient skin accumulation of Compound 1 to inhibit HSP-90 in the skin and thereby treat discoid lupus erythematosus, systemic lupus erythematosus, or subacute cutaneous lupus erythematosus. The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are hereby incorporated by reference.

[0061] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus or systemic lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method is for treating diffuse discoid lupus erythematosus.

3. The method of claim 1, wherein the method is for treating subacute cutaneous lupus.

4. The method of claim 1, wherein the method is for treating systemic lupus erythematosus with cutaneous manifestations.

5. The method of claim 1, wherein the method is for treating bullous systemic lupus erythematosus.

6. The method of any one of claims 1 to 5, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered to the subject orally.

7. The method of claim 6, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 0.5 mg to 400 mg per day.

8. The method of claim 7, wherein the free base equivalent dose is 200 mg to 300 mg per day.

9. The method of claim 7, wherein the free base equivalent dose is 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

10. The method of claim 8, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

11. The method of any one of claims 6 to 10, wherein Compound 1 or the pharmaceutically acceptable salt thereof, is administered in the form of a tablet.

12. The method of claim 6, wherein the Compound 1 or the pharmaceutically acceptable salt thereof, is administered in the form of a tablet comprising 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or the pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1 to 5, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered topically.

14. The method of claim 13, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered at a free base equivalent dose of 0.5 mg to 400 mg per day.

15. The method or compound of claim 13 or claim 14, wherein Compound 1 or the pharmaceutically acceptable salt thereof, is topically administered in the form of a cream,a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

16. The method of claim 14 or 15, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

17. A compound which is Compound 1,or a pharmaceutically acceptable salt thereof, for use in a method of treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus or systemic lupus erythematosus in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or salt thereof.

18. The compound or pharmaceutically acceptable salt thereof for use of claim 17, wherein the method is for treating diffuse discoid lupus erythematosus.

19. The compound or pharmaceutically acceptable salt thereof for use of claim 17, wherein the method is for treating subacute cutaneous lupus.

20. The compound or pharmaceutically acceptable salt thereof for use of claim 17, wherein the method is for treating systemic lupus erythematosus with cutaneous manifestations.

21. The compound or pharmaceutically acceptable salt thereof for use of claim 20, wherein the method is for treating bullous systemic lupus erythematosus.

22. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 17 to 21, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered to the subject orally or topically.

23. The compound or pharmaceutically acceptable salt thereof for use of claim 22, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 0.5 mg to 400 mg per day.

24. The compound or pharmaceutically acceptable salt thereof for use of claim 23, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

25. The compound or pharmaceutically acceptable salt thereof for use of claim 23, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

26. The compound or pharmaceutically acceptable salt thereof for use of claim 25, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

27. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 23 to 26, wherein Compound 1 or the pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets.

28. The compound or pharmaceutically acceptable salt thereof for use of claim 23, wherein the compound or pharmaceutically acceptable salt thereof is administered in the form of one or more tablets comprising from 0.5 mg to 400 mg, from 1 mg to 350 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mgor 250 mg free base equivalent amount of Compound 1 or the pharmaceutically acceptable salt thereof.

29. The compound or pharmaceutically acceptable salt thereof for use of claim 22, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered topically.

30. The compound or pharmaceutically acceptable salt thereof for use of claim 29, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered at a free base equivalent dose of 0.5 mg to 400 mg per day.

31. The compound or pharmaceutically acceptable salt thereof for use of claim 29 or claim 30, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via a transdermal patch or an iontophoresis device.

32. The compound or pharmaceutically acceptable salt thereof for use of claim 31, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered topically to the subject at a free base equivalent dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

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