Methods of treating vexas

Abstract

The present disclosure provides a method of treating VEXAS syndrome, comprising administering pacritinib or a pharmaceutically acceptable salt thereof to a subject.

Description

[0001] METHODS OF TREATING VEXAS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 670,409, filed on July 12, 2024, the contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND OF THE INVENTION

[0005] VEXAS syndrome is an autoinflammatory hematological disease arising from a mutation of the UBA1 gene. More specifically, VEXAS is an acronym describing the identifying features of the syndrome: Vacuoles are often seen in cells identified in bone marrow biopsies from patients, symptoms arising from differences in the El ubiquitin activating enzyme caused by mutation of the UBA1 gene, the UBA1 gene is located on the X chromosome, patients have autoinflammation, and finally, the mutations are somatic, meaning they are acquired at some point in life and are not inherited.

[0006] There remains a need for an effective therapeutic approach for the treatment of VEXAS.

[0007] SUMMARY OF THE INVENTION

[0008] In certain aspects, the present disclosure provides a method of treating VEXAS syndrome, comprising administering pacritinib or a pharmaceutically acceptable salt thereof to a subject.

[0009] DETAILED DESCRIPTION OF THE INVENTION

[0010] UBA1 is normally involved in ubiquitin signaling, targeting proteins for degradation and membrane trafficking. The typical mutation associated with VEXAS affects methionine- 41 and results in lack of cytoplasmic expression of the corresponding protein. Autoimmune and hematologic manifestations ensue, possibly as a result of impaired protein degradation. The inflammatory signature of VEXAS, which includes significantly elevated levels of IL- 1b, IL-6, IL-8, and TNFa, suggests that disease-related inflammation may be mediated by NFKB. Indeed, patients have elevated plasma levels of calprotectin (the alarmins S100A8 / 9), which signals through the myddosome to activate NFKB.

[0011] Consequently, patients with VEXAS can experience a wide range of inflammatory symptoms affecting multiple organs including: skin (rashes that can be painful), cartilaginous structures (pain and swelling of the ear and nose), lungs (cough and shortness of breath), joints (swelling and pain), vasculature (inflammation of vessels). Systemic inflammation may cause patients to experience global symptoms including fever and extreme fatigue. The hematologic features of VEXAS can include anemia, low platelets, and blood clots. On many occasions patients with VEXAS have associated clinical diagnoses, including relapsing polychondritis, polyarteritis nodosa, sweet syndrome and myelodysplastic syndrome. Additionally, VEXAS syndrome is associated with substantial mortality.

[0012] There is no established treatment for VEXAS syndrome. Current standard of care involves chronic use of glucocorticoids (GCs), often at moderate or high doses. GCs are almost always required to mitigate inflammatory manifestations, with flares occurring if doses are tapered. Prolonged use of high-dose GCs presents many added challenges, as patients experience toxicity in multiple organ systems and long-term adverse events.

[0013] A variety of GC-sparing strategies have been attempted, including cyclosporine, methotrexate, anti-IL-1, anti -IL-6, anti-TNFa, Janus kinase (JAK) inhibition, and hypomethylating agents, with variable success. While use and selection of GC-sparing strategies is not uniform across clinical practices, emerging data suggests that JAK inhibitors may be at least partially effective: the JAK1 / 2 inhibitor ruxolitinib was associated with improvement in disease manifestations in a small cohort of patients. However, the doses of ruxolitinib required to control inflammation in this study were high (up to 25-30 mg twice daily), and drug-induced cytopenias were common. The role of allogeneic hematopoietic stem cell transplantation in treatment of VEXAS syndrome is still being evaluated; the only interventional study in VEXAS currently listed in clinicaltrials.gov is a transplant trial being conducted at the National Institutes of Health (NCT05027945).

[0014] There is an unmet need for novel therapies for patients with VEXAS that ameliorate the signs and symptoms of disease while allowing for GC taper.

[0015] Pacritinib is a kinase inhibitor with the chemical name (2E,16E)-l l-[2-(pyrrolidin-l- yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6). l(8,12)]heptacosa-

[0016] l(25),2,4,6,8,10,12(26),16,21,23-decaene. The molecular formula is C28H32N4O3 and the structural formula is:

[0017] Pacritinib is a potent, selective inhibitor of JAK2 and IRAKI kinase activities (IC50 = 6 nM and 13.6 nM, respectively), as well as activity against CSF1R (IC50 = 39.5nM), ACVR1 (IC50 = 16.7nM), and FLT3 (IC50 = 14.8 nM). Pacritinib is also a potent inhibitor of cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on the target kinases (cellular IC50 ranges from 0.03 to 0.24 pM). At clinically relevant concentrations, pacritinib does not inhibit JAK1.

[0018] In some embodiments, the present disclosure provides a method of treating VEXAS syndrome, comprising administering pacritinib or a pharmaceutically acceptable salt thereof to a subject.

[0019] In some embodiments, the pacritinib is administered in a total daily dose of from 50 mg to 400 mg. In some embodiments, the total daily dose is from 55 mg to 400 mg. In some embodiments, the total daily dose is from 60 mg to 400 mg. In some embodiments, the total daily dose is from 65 mg to 400 mg. In some embodiments, the total daily dose is from 75 mg to 400 mg. In some embodiments, the total daily dose is from 100 mg to 400 mg. In some embodiments, the total daily dose is from 125 mg to 400 mg. In some embodiments, the total daily dose is from 150 mg to 400 mg. In some embodiments, the total daily dose is from 200 mg to 400 mg. In some embodiments, the total daily dose is from 300 mg to 400 mg. In some embodiments, the total daily dose is from 50 mg to 400 mg. In some embodiments, the total daily dose is from 50 mg to 300 mg. In some embodiments, the total daily dose is from 50 mg to 200 mg. In some embodiments, the total daily dose is from 50 mg to 100 mg. In some embodiments, the total daily dose is from 50 mg to 125 mg. In some embodiments, the total daily dose is from 100 mg to 300 mg. In some embodiments, the total daily dose is from 150 mg to 400 mg. In some embodiments, the total daily dose is from 175 mg to 325 mg. In some embodiments, the total daily dose is from 175 mg to 225 mg. In some embodiments, the total daily dose is about 100 mg. In some embodiments, the total daily dose is about 150 mg. In some embodiments, the total daily dose is about 200 mg. In some embodiments, the total daily dose is about 225 mg. In some embodiments, the total daily dose is about 250 mg. In some embodiments, the total daily dose is about 275 mg. In some embodiments, the total daily dose is about 300 mg. In some embodiments, the total daily dose is about 325 mg. In some embodiments, the total daily dose is about 350 mg. In some embodiments, the total daily dose is about 375 mg. In some embodiments, the total daily dose is about 400 mg.

[0020] In some embodiments, the total daily dose is administered in one dose per day (QD). In some embodiments, the total daily dose is administered in one dose of about 50 mg per day. In some embodiments, the total daily dose is administered in one dose of about 75 mg per day. In some embodiments, the total daily dose is administered in one dose of about 100 mg per day. In some embodiments, the total daily dose is administered in one dose of about 125 mg per day. In some embodiments, the total daily dose is administered in one dose of about 150 mg per day. In some embodiments, the total daily dose is administered in one dose of about 175 mg per day. In some embodiments, the total daily dose is administered in one dose of about 200 mg per day. In some embodiments, the total daily dose is administered in one dose of about 225 mg per day. In some embodiments, the total daily dose is administered in one dose of about 250 mg per day. In some embodiments, the total daily dose is administered in one dose of about 275 mg per day. In some embodiments, the total daily dose is administered in one dose of about 300 mg per day. In some embodiments, the total daily dose is administered in one dose of about 350 mg per day. In some embodiments, the total daily dose is administered in one dose of about 400 mg per day.

[0021] In some embodiments, the total daily dose is administered in two or more doses per day. In some embodiments, the total daily dose is administered in two doses per day (BID). In some embodiments, the total daily dose is administered as two doses of about 25 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 50 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 75 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 100 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 125 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 150 mg each per day. In some embodiments, the total daily dose is administered as two doses of about 200 mg each per day. In some embodiments, the total daily dose is administered in three doses per day. In some embodiments, the compound is administered orally. In some embodiments, the compound is administered parenterally.

[0022] In some embodiments, the pacritinib is a free base having a molecular weight of about 472.59 g / mol. In some embodiments, the pacritinib is administered as a pharmaceutically acceptable salt, and the total daily dose of pacritinib is calculated based on the molecular weight of the free base. Thus, the quantity of pacritinib salt to be administered is calculated by multiplying the desired quantity of pacritinib free base by the ratio of the molecular weight of the salt divided by the molecular weight of the free base.

[0023] In some embodiments, the pacritinib is a citrate salt, pacritinib citrate. In some embodiments, the pacritinib citrate has a molecular weight of about 664.7 g / mol. In such embodiments, the total daily dose of pacritinib is calculated based on the molecular weight of the citrate salt. Thus, the quantity of pacritinib citrate salt is calculated by multiplying the desired administration quantity of pacritinib free base by 1.4065, to yield the total mg of pacritinib citrate equivalent.

[0024] In some embodiments, the pacritinib is administered orally in the form of a gelatin capsule. Each capsule can comprise, for example, 100 mg of pacritinib, e.g., as 140.65 mg of pacritinib citrate. In some embodiments, the gelatin capsule also comprises inactive ingredients such as microcrystalline cellulose NF, polyethylene glycol 8000 (PEG 8000) NF, and magnesium stearate NF.

[0025] In some embodiments, a glucocorticoid is administered conjointly with the pacritinib. In some embodiments, the glucocorticoid is prednisone or prednisolone. In some embodiments, the total daily dose of glucocorticoid is from 1 mg to 100 mg. In some embodiments, the total daily dose of glucocorticoid is from 1 mg to 25 mg. In some embodiments, the total daily dose of glucocorticoid is from 0.5 mg to 25 mg. In some embodiments, the total daily dose of glucocorticoid is from 0.5 mg to 50 mg. In some embodiments, the total daily dose of glucocorticoid is from 0.5 mg to 10 mg. In some embodiments, the total daily dose of glucocorticoid is from 5 mg to 10 mg. In some embodiments, the total daily dose of glucocorticoid is from 10 mg to 20 mg. In some embodiments, the total daily dose of glucocorticoid is from 15 mg to 25 mg. In some embodiments, the total daily dose of glucocorticoid is from 10 mg to 30 mg. In some embodiments, the total daily dose of glucocorticoid is from 15 mg to 45 mg. In some embodiments, the total daily dose of glucocorticoid is from 20 mg to 30 mg. In some embodiments, the total daily dose of glucocorticoid is from 25 mg to 45 mg. In some embodiments, the total daily dose of glucocorticoid is from 30 mg to 50 mg. In some embodiments, the total daily dose of glucocorticoid is from 50 mg to 100 mg.

[0026] In some embodiments, the total daily dose of glucocorticoid is about 12.5 mg. In some embodiments, the total daily dose of glucocorticoid is about 15 mg. In some embodiments, the total daily dose of glucocorticoid is about 17.5 mg. In some embodiments, the total daily dose of glucocorticoid is about 22.5 mg. In some embodiments, the total daily dose of glucocorticoid is about 27.5 mg. In some embodiments, the total daily dose of glucocorticoid is about 30 mg. In some embodiments, the total daily dose of glucocorticoid is about 35 mg. In some embodiments, the total daily dose of glucocorticoid is about 35 mg.

[0027] In some embodiments, the total daily dose of glucocorticoid is 100 mg or less. In some embodiments, the total daily dose of glucocorticoid is 50 mg or less. In some embodiments, the total daily dose of glucocorticoid is 40 mg or less. In some embodiments, the total daily dose of glucocorticoid is 30 mg or less. In some embodiments, the total daily dose of glucocorticoid is 25 mg or less. In some embodiments, the total daily dose of glucocorticoid is 20 mg or less. In some embodiments, the total daily dose of glucocorticoid is 15 mg or less. In certain preferred embodiments, the total daily dose of glucocorticoid is 10 mg or less. In some embodiments, the total daily dose of glucocorticoid is 7.5 mg or less. In some embodiments, the total daily dose of glucocorticoid is 5 mg or less. In some embodiments, the total daily dose of glucocorticoid is 1 mg or less. In some embodiments, the total daily dose of glucocorticoid is 0.5 mg or less.

[0028] In some preferred embodiments, a glucocorticoid is not administered conjointly with the pacritinib.

[0029] In some embodiments, the pacritinib is administered on a daily schedule as described herein for 12 weeks. In some embodiments, the pacritinib is administered for 24 weeks. In some embodiments, the pacritinib is administered for 36 weeks. In some embodiments, the pacritinib is administered for 48 weeks. In some embodiments, the pacritinib is administered for 52 weeks. In some embodiments, the pacritinib is administered for 24 weeks, 36 weeks, 48 weeks, 52 weeks, 54 weeks, 56 weeks, 58 weeks, 60 weeks, 62 weeks, 64 weeks, 66 weeks, 68 weeks, 70 weeks, 72 weeks, 74 weeks, 76 weeks, 78 weeks, 80 weeks, 82 weeks, 84 weeks, 86 weeks, 88 weeks, 90 weeks, 92 weeks, 94 weeks, 96 weeks, 98 weeks, 100 weeks, 102 weeks, 104 weeks, 106 weeks, 108 weeks, 110 weeks, 112 weeks, 114 weeks, 116 weeks, 118 weeks, 120 weeks, 122 weeks, 124 weeks, 126 weeks, 128 weeks, 130 weeks, 132 weeks, 134 weeks, 136 weeks, 138 weeks, 140 weeks, 142 weeks, 144 weeks, 146 weeks, 148 weeks, 150 weeks, 152 weeks, 154 weeks, 156 weeks, 158 weeks, 160 weeks, 162 weeks, 164 weeks, 166 weeks, 168 weeks, 170 weeks, 172 weeks, 174 weeks, 176 weeks, 178 weeks, 180 weeks, 182 weeks, 184 weeks, 186 weeks, 188 weeks, 190 weeks, 192 weeks, 194 weeks, 196 weeks, 198 weeks, or 200 weeks. In some embodiments, the pacritinib is administered for 2 years. In some embodiments, the pacritinib is administered for 3 years.

[0030] Pharmaceutical Compositions

[0031] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a human. When administered, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, pacritinib and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as a tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system (e.g., a skin patch). The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0032] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, to increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0033] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0034] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0035] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (e.g., as drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules [including sprinkle capsules and gelatin capsules], boluses, powders, granules, or pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (e.g., as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0036] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0037] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0038] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0039] To prepare solid dosage forms for oral administration (capsules [including sprinkle capsules and gelatin capsules], tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high-molecular-weight polyethylene glycols and the like.

[0040] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), or surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0041] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0042] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0043] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0044] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0045] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, oral spray, or oral ointment.

[0046] Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0047] Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0048] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams, and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0049] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0050] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0051] Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0052] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0053] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0054] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0055] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0056] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0057] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5%, more preferably, 0.5 to 90%, of active ingredient in combination with a pharmaceutically acceptable carrier.

[0058] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0059] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0060] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout a day, optionally, in unit dosage forms. In preferred embodiments of the present invention, an active compound may be administered one or two times daily on the days on which it is administered.

[0061] In certain embodiments, the methods of the invention may be used alone or the compounds administered may be used conjointly with another type of therapeutic agent.

[0062] This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxy -2 -naphthoic acid, 2, 2-di chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, L- pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0063] The pharmaceutically acceptable acid-addition salts, or the free base form, can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0064] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0065] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BEIT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, Vitamin E-TPGS, and the like.

[0066] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0067] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0068] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0069] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0070] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0071] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow-release formulation, or administered using a device for such slow or extended release.

[0072] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0073] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0074] EXAMPLES

[0075] The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0076] Example 1: Clinical Study of Pacritinib for VEXAS

[0077] A randomized, double-blind, placebo-controlled, dose-finding phase 2 study (Part 1) followed by an open-label period (Part 2) to assess the efficacy and safety of pacritinib in patients with VEXAS syndrome is conducted. See, “A Study to Assess the Effectiveness and Safety of Pacritinib in Patients with VEXAS Syndrome (PAXIS)” ClinicalTrials.gov Identifier: NCT06782373. Study Design

[0078] Approximately 78 VEXAS patients are randomized 1 : 1 : 1 to receive pacritinib 200 mg twice daily (BID) (n=26), pacritinib 100 mg BID plus placebo 1 capsule BID (n=26), or placebo 2 capsules BID (n=26) for up to 24 weeks. Randomization will be stratified by prescribed GC dose on the day of randomization (15 to 25 mg vs. >25 to 45 mg daily).

[0079] Double-blind Period

[0080] Patients will follow a fixed GC taper based on their GC dose at randomization. All schedules start with an escalation of the GC dose followed by a taper. Patients may require GC rescue therapy for VEXAS flares if deemed necessary by the investigator. GC therapy should be re-tapered after flare resolution. Patients must discontinue double-blind treatment at the End of Week 12 if Early Failure criteria are met. Patients who complete the doubleblind treatment period at End of Week 24 or meet Early Failure criteria at End of Week 12 will transition to an open-label treatment period.

[0081] Open-label Period

[0082] Patients who complete the double-blind treatment period at End of Week 24 or meet Early Failure criteria at End of Week 12 will transition to an open-label treatment period and will be dosed with pacritinib 200 mg BID through End of Week 48. If the 200 mg BID arm previously closed due to interim futility or safety rules, patients transitioning to open-label treatment will receive pacritinib 100 mg BID in an open-label fashion, and patients currently receiving pacritinib 200 mg BID in the open-label period will reduce their dose to 100 mg BID For all patients transitioning to open-label treatment, GC taper will pause for 3 weeks before continuing.

[0083] Inclusion Criteria

[0084] 1. Age >18 years at the time of signing the informed consent form (ICF).

[0085] 2. Documented evidence of pathogenic myeloid methionine-41 (M41) or splice site mutation in UBA1 based on myeloid NGS, polymerase chain reaction (PCR), or Sanger sequencing.

[0086] 3. Current or documented evidence of past inflammatory involvement within 6 months prior to enrollment of at least one of the following organ systems by VEXAS syndrome: cutaneous (e.g., neutrophilic dermatosis, cutaneous vasculitis), vasculature (e.g., vasculitis), musculoskeletal (e.g., chondritis, arthritis), ocular (e.g., uveitis, scleritis), periorbital (e.g., periorbital edema), genitourinary (e.g., epididymitis), or pulmonary (e.g., alveolitis).

[0087] Note: Other inflammatory signs may be considered for enrollment at the discretion of the Investigator with Medical Monitor approval provided that these signs have been previously demonstrated to be GC-responsive (i.e., resolve after administration of or escalation in GC therapy). Receiving ongoing GC therapy (with prednisone or prednisolone) for >4 consecutive weeks leading up to enrollment for the treatment of VEXAS syndrome. Prednisone or prednisolone Baseline Dose of 15-45 mg / day that has been stable for >10 days prior to enrollment. Note that patients who are stable on GC doses of 10-14 mg daily in addition to another non-GC anti-inflammatory therapy at screening who have a previously documented VEXAS flare on GC monotherapy at a dose of >10 mg may be eligible provided that their GC dose is escalated to 15-45 mg daily after washout, and that this dose is stable for >10 days prior to enrollment. Karnofsky Performance Status >50% Adequate organ function, meeting all the following criteria within 30 days prior to enrollment: a. Aspartate aminotransferase [AST] and alanine aminotransferase [ALT] [SGPT]) <3 x upper limit of normal (ULN) b. Total bilirubin <4 x ULN (<8 x ULN in the setting of Gilbert’s syndrome) c. Creatinine clearance >30 mL / min based on the Cockcroft-Gault formula d. Absolute neutrophil count >500 / pL e. Prothrombin time (PT) or international normalized ratio (INR) <1.5 x ULN (unless prolonged due to therapeutic anti coagulation) f. Partial thromboplastic time (PTT) or activated PTT <1.5 x ULN (unless prolonged due to therapeutic anti coagulation) g. Platelet count >25 x 109 / L h. Peripheral blasts <5% Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 30 days prior to enrollment and a negative urine pregnancy test on Day 1 prior to randomization and dosing. 9. WOCBP and male patients must agree to use a highly effective method of contraception starting at the first dose of study therapy through 90 days after the last dose of study therapy.

[0088] 10. Able and willing to comply with protocol requirements, including but not limited to: completing in-person study visits, recording daily prednisone / prednisolone use in diary, undergoing trial-related procedures, and completing patient-reported outcome assessments.

[0089] 11. Provision of signed informed consent.

[0090] Efficacy Assessments

[0091] Day 1 assessments are performed pre-dose. At visits on End of Weeks 4, 12, and 24, laboratory tests are collected pre-dose along with pre-dose PK assessments. Post-dose PK assessments at End of Weeks 4 and 12 are assessed at specified intervals post-dose. Other study assessments may be performed pre- or post-dose.

[0092] • A Prednisone / Prednisolone Dose Diary is completed daily by the patient and reviewed with the investigator at each study visit and remote contact. Data collection starts at least 10 days prior to enrollment and continues through the 30-days Post-EOT visit (double-blind and open label treatment periods) or until receipt of another non- GC anti-inflammatory therapy that is prohibited on study, whichever occurs earlier.

[0093] • VEXAS Flares are assessed and documented by the investigator during screening, throughout treatment, and through 30-days Post-EOT (double-blind and open label treatment periods).

[0094] • Complete blood count (CBC) with differential to assess hematologic improvement (schedule described below under Safety Assessments) and transfusion documentation, including baseline history (transfusions received within 90 days prior to enrollment) as well as transfusions occurring throughout study treatment (doubleblind and open label treatment periods).

[0095] • Quality of life and symptom assessment during the double-blind period based on the following patient-reported outcome (PRO) instruments: PROMIS short forms (fatigue, physical function, sleep disturbance, cognitive function), SF-36, EQ-5D-5L, Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGI-S), and the VEXAS Symptom Assessment Form (SAF). These instruments are administered during screening (all except PGIC), on Day 1 (all except PGIC), and every 4 weeks.

[0096] • Disease activity based on Clinical Global Impression of Change (CGI-C) and Clinical Global Impression of Severity (CGI-S) are assessed during the double-blind period. CGI will be assessed by the investigator during screening (CGI-S only), on Day 1 (CGI-S only), and every 4 weeks (both instruments).

[0097] • VEXAS-Disease Activity Index (DAI) are assessed during screening, on Day 1, and at every scheduled in-person study visit (e.g., End of Weeks 4, 8, 12, etc.) during the double-blind treatment period. Additional assessment points are captured if patients present for unscheduled in-person study visits during a flare.

[0098] • Performance status based on the Karnofsky performance scale are assessed during Screening, on Day 1, and every 4 weeks during the double-blind treatment period.

[0099] • Glucocorticoid Toxicity Index (GTI) is a composite measure based on laboratory results (LDL, hemoglobin Ale), vital signs, body mass index (weight, height), change in medications (for blood pressure, diabetes, hyperlipidemia), a myopathy assessment (physical exam), a skin toxicity assessment (physical exam), a neuropsychiatric assessment (patient interview), and an assessment of infections. GTI assessments are performed on Day 1 and End of Weeks 12 and 24 (double-blind period only).

[0100] • Inflammatory markers (CRP, ESR, and ferritin) are assessed in screening, on Day 1, at all in-person study visits (End of Weeks 4, 8, etc.), at EOT, and at the 30-day post- EOT visit (double-blind and open label treatment periods). In addition, these inflammatory markers are assessed during VEXAS flares.

[0101] • Specialized disease markers (central lab) are assessed based on peripheral blood on Day 1 and End of Weeks 12 and 24 (during the double-blind treatment period only).

[0102] • Myeloid and VBA1 mutation testing (central lab), including allele frequency, are performed on peripheral blood on Day 1 and End of Week 24 (during the doubleblind treatment period only).

[0103] • Pharmacokinetic (PK) assessments (central lab): blood samples for PK assessments are collected at the End of Week 4 (pre-dose, 4 hours post-dose, and 6 hours post-dose), Week 12 (pre-dose, 4 hours post-dose, and 6 hours post-dose), and Week 24 (pre-dose only) during the double-blind treatment period only.

[0104] • Exit interview at the end of the double-blind treatment period within 14 days after last double-blind dose. Dose and Mode of Administration

[0105] Double-blind treatment period: pacritinib 200 mg BID or pacritinib 100 mg BID plus placebo 1 capsule BID or placebo 2 capsules BID administered orally for up to 24 weeks.

[0106] Open label treatment period: pacritinib 200 mg BID. If the pacritinib 200 mg BID treatment arm is terminated, pacritinib 100 mg BID will be used for the open label period. All patients currently on open label pacritinib will transition to 100 mg BID (unless previously dose reduced); all patients starting open label pacritinib will start on 100 mg BID All patients who have dose reduced while on the double-blind treatment period will start pacritinib at 100 mg BID during the open-label period. The open label period will start at either End of week 24 (after double-blind period) or End of Week 12 (for patients meeting Early Failure criteria) and will continue through End of Week 48.

[0107] GC dosage: 15-45 mg daily (prednisone or prednisolone) is maintained at a stable dose for >10 days prior to enrollment. GC administration will be continued during study treatment and administered as part of a fixed taper. Patients may be completely tapered off GC during the study, at which point they will be receiving pacritinib monotherapy.

[0108] INCORPORATION BY REFERENCE

[0109] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0110] EQUIVALENTS

[0111] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the methods of treatment described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. Those skilled in the art will also recognize that all combinations of embodiments described herein are within the scope of the invention.

Claims

We claim:

1. A method of treating VEXAS syndrome, comprising administering pacritinib or a pharmaceutically acceptable salt thereof to a subject.

2. The method of claim 1, wherein the pacritinib is administered at a total daily dose of from 50 mg to 400 mg.

3. The method of claim 2, wherein the total daily dose of pacritinib is from 100 mg to 400 mg.

4. The method of claim 2 or claim 3, wherein the total daily dose of pacritinib is 100 mg.

5. The method of claim 2 or claim 3, wherein the total daily dose of pacritinib is 200 mg.

6. The method of claim 2 or claim 3, wherein the total daily dose of pacritinib is 400 mg.

7. The method of any one of claims 2-6, wherein the total daily dose is administered in two doses per day (BID).

8. The method of claim 7, wherein the total daily dose is administered as two doses of 100 mg each per day.

9. The method of claim 7, wherein the total daily dose is administered as two doses of 200 mg each per day.

10. The method of any one of claims 2-6, wherein the total daily dose is administered in one dose per day (QD).

11. The method of claim 10, wherein the total daily dose is administered as one dose of 100 mg per day.

12. The method of any one of the preceding claims, wherein the pacritinib is a citrate salt of pacritinib.

13. The method of any one of the preceding claims, wherein the method further comprises administering a glucocorticoid conjointly with the pacritinib.

14. The method of claim 13, wherein the glucocorticoid is prednisone or prednisolone.

15. The method of claim 13 or 14, wherein the total daily dose of glucocorticoid is 100 mg or less.

16. The method of claim 15, wherein the total daily dose of glucocorticoid is from 0.5 mg to 50 mg.

17. The method of claim 13, wherein the total daily dose of glucocorticoid is 25 mg or less.

18. The method of claim 17, wherein the total daily dose of glucocorticoid is from 0.5 mg to 25 mg.

19. The method of claim 13, wherein the total daily dose of glucocorticoid is 10 mg or less.

20. The method of claim 19, wherein the total daily dose of glucocorticoid is from 0.5 mg to 10 mg.

21. The method of any one of claims 1-12, wherein the subject is not receiving a glucocorticoid conjointly with the pacritinib.

22. The method of any one of claims 1-21, wherein the pacritinib is administered over a period of 48 weeks.

23. The method of any one of claims 1-21, wherein the pacritinib is administered over a period of 152 weeks.

24. The method of any one of claims 1-21, wherein the pacritinib is administered over a period of about 3 years.

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