Combination therapy comprising anti-IL-23 antibodies and corticosteroids for treating psoriasis - Patent Application 20070123333

Abstract

The present disclosure relates to the combination of the anti-IL-23 antibody tildrakizumab in combination with a corticosteroid for use in the treatment of plaque psoriasis.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 299,181, filed January 13, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides a combination therapy comprising an IL-23 antagonist and a corticosteroid. The combination therapy of the present invention is useful for treating, preventing, or alleviating psoriasis vulgaris. The addition of a corticosteroid to an IL-23 inhibitor therapy enhances the anti-psoriasis therapeutic effect of the IL-23 inhibitor. [Background technology]

[0003] Psoriasis is a chronic inflammatory skin disease that affects approximately 3% of adults in the United States (JAMA Dermatol. 2021; 157(8):940-946). It is characterized by marked inflammation and increased epithelial thickness resulting from infiltration of activated T cells into the skin and abnormal proliferation and differentiation of keratinocytes. Moderate to severe psoriasis is associated with many comorbidities, including metabolic syndrome, cardiovascular and cerebrovascular disease, depression, and anxiety (Acad Dermatol. 2017; 76(3):377-390). Patients may also develop mental health conditions and have a reduced quality of life (Patient Relat Outcome Meas. 2015; 6167-177).

[0004] Treatment options include topical therapy for limited psoriasis, and phototherapy, systemic agents, and biologics for widespread psoriasis (J Am Acad Dermatol. 2008; 58(5):826-850). For plaque psoriasis, the National Psoriasis Foundation suggests an acceptable treatment response of 3% or less of affected body surface area (BSA) after 3 months of treatment, and a target response of 1% or less of BSA (J Am Acad Dermatol. 2017; 76(2):290-298).

[0005] Drugs that inhibit TNF-α include the biologics infliximab (REMICADE®), adalimumab (HUMIRA®), and etanercept (ENBREL®), which are approved for the treatment of psoriasis. Inflixmab and adalimumab are chimeric and fully human antibodies, respectively, that bind to human TNF-α. Etanercept is a fusion protein consisting of the extracellular domain of the human p75 TNF receptor fused to the Fe portion of the antibody, which is currently used as a systemic treatment for moderate to severe plaque psoriasis.

[0006] Among biologics, tildrakizumab is a humanized IgG1 monoclonal antibody that selectively binds to interleukin-23 (IL-23) and inhibits its receptor interaction. Randomized, controlled trials have shown that tildrakizumab monotherapy is effective compared with placebo for the treatment of psoriasis and is well tolerated in patients with chronic moderate to severe plaque psoriasis. However, in a cohort study, nearly half of patients did not achieve BSA 3% with tildrakizumab monotherapy at week 16.

[0007] Surprisingly, the present inventors have found that adjunctive use of topical halcinonide ointment for 4 weeks effectively improves all outcomes in these patients, reflected in decreases in mean BSA, PGA, and BSA x PGA, and an increase in the proportion of all patients with a BSA 3% or less from Week 16 to Week 20. Moreover, the enhanced response is maintained through Week 24 after the additional halcinonide ointment is discontinued for 4 weeks. Furthermore, the inventors have found that a patient's response to tildrakizumab can be enhanced with the addition of halcinonide ointment without the need to increase the tildrakizumab dose or switch to a new biologic agent. Summary of the Invention

[0008] Thus, the present invention provides a combination therapy comprising an IL-23 antagonist and a corticosteroid. The combination therapy of the present invention is useful for treating, preventing, or alleviating psoriasis vulgaris. The addition of a corticosteroid to an IL-23 inhibitor therapy enhances the anti-psoriasis therapeutic effect of the IL-23 inhibitor.

[0009] Thus, the invention provides one or more of the following embodiments.

[0010] In one embodiment, the present invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, the method comprising: PASI score of 12 or more; 10% or more of the body surface area (BSA) affected by psoriasis, and / or selecting patients having a PGA score of 3 or greater; administering to said patient an IL-23 inhibitor at a dose of about 100 milligrams by subcutaneous injection at weeks 0, 4, and 16; At week 16, patients with a BSA greater than 3% were administered corticosteroids twice daily for four weeks, followed by continued follow-up without corticosteroids for an additional four weeks. and describing the changes from baseline in BSA, PGA, PGAxBSA, PSAI, and DLQI, wherein the method achieves a BSA level of 1% or less to 3% or less at week 20 and maintains that level of response through week 24 in patients receiving corticosteroids.

[0011] In another embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis vulgaris, wherein the percent reduction from baseline in mean BSA, PGA, and PGA x BSA is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and response is maintained at 24 weeks after corticosteroid therapy is stopped for 4 weeks.

[0012] In yet another embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein the percent reduction from baseline in PSAI (75, 90 and 100) is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and the response is maintained at 24 weeks after corticosteroid therapy has been discontinued for 4 weeks.

[0013] In yet another embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis vulgaris, wherein the reduction from baseline in DLQI is significantly increased at week 20 after 4 weeks of adjunctive corticosteroid therapy, and the response is maintained at week 24, after corticosteroid therapy has been stopped for 4 weeks.

[0014] In yet another embodiment, the present invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein a corticosteroid is administered as a topical preparation.

[0015] In one embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein the topical preparation is in the form of an ointment, powder, gel ointment, emollient, cream, adhesive patch or strip, shampoo, spray, foam, gel, liquid, or solution.

[0016] In another embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein a corticosteroid is administered as an ointment, preferably a 0.1% ointment.

[0017] In yet another embodiment, the present invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein the corticosteroid is selected from beclomethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clobetasol propionate, clocortolone acetate, clocortolone pivalate, corticosterone, cortisone, ethoximethasone acetate fluocinolone acetonide, halcinonide, halobetasol propionate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone phosphate, hydrocortisone sodium succinate, methylprednisolone acetate, prednisolone, or prednisone. In one embodiment, the corticosteroid is halcinonide. In another embodiment, the corticosteroid is prednisone.

[0018] In yet another embodiment, the present invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein the IL-23 inhibitor is selected from guselkumab, risankizumab, or tildrakizumab.

[0019] In another embodiment, the invention provides a method for treating a patient suffering from moderate to severe plaque psoriasis, wherein the IL-23 antagonist is tildrakizumab.

[0020] In yet another embodiment, the invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist comprising continuing treatment with the IL-23 antagonist, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing a corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the percentage of patients achieving a BSA of 3% or less increases after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to the IL-23 antagonist alone, and said improvement is maintained four weeks after corticosteroid treatment is stopped.

[0021] In yet another embodiment, the invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the percent reduction from baseline in mean BSA, PGA, and PGA x BSA is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, the percent reduction from baseline in PSAI (75, 90, and 100) is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, the percent reduction from baseline in DLQI is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and said response (all outcomes) is maintained at 24 weeks after corticostreoid therapy is stopped for 4 weeks.

[0022] In yet another embodiment, the invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the patient continues treatment with the IL-23 antagonist for at least about 16 weeks.

[0023] In yet another embodiment, the invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the IL-23 antagonist is guselkumab, risankizumab, or tildrakizumab.

[0024] In yet another embodiment, the present invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the IL-23 antagonist is tildrakizumab.

[0025] In yet another embodiment, the present invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein a corticosteroid is administered as a topical preparation.

[0026] In one embodiment, the invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the topical preparation is in the form of an ointment, powder, gel ointment, emollient, cream, adhesive patch or strip, shampoo, spray, foam, gel, liquid, or solution.

[0027] In yet another embodiment, the present invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the corticosteroid is selected from beclomethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clobetasol propionate, clocortolone acetate, clocortolone pivalate, corticosterone, cortisone, ethoximethasone acetate fluocinolone acetonide, halcinonide, halobetasol propionate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone phosphate, hydrocortisone sodium succinate, methylprednisolone acetate, prednisolone, prednisone, or halcinonide, preferably halcinodine.

[0028] In yet another embodiment, the present invention provides a method for treating a psoriasis patient receiving an IL-23 antagonist, wherein the corticosteroid is halcinonide ointment, preferably a 0.1% ointment. [Brief description of the drawings]

[0029] [Figure 1] Percentage of patients achieving BSA ≤3% and BSA ≤1% at weeks 16, 20, and 24 among all patients (A) and among patients with a BSA >3% who received halcinonide at week 16 (B). [Diagram 2] Mean BSA involvement at different time points for all patients, patients with BSA 3% or less at week 16, and patients with BSA > 3% at week 16 (n indicates the number of patients with available data for each study visit). [Diagram 3] Mean PGA scores at different time points for all patients, patients with BSA 3% or less at week 16, and patients with BSA > 3% at week 16 (n indicates the number of patients with available data for each study visit). [Figure 4] Mean PGA x BSA at different time points for all patients, patients with BSA 3% or less at week 16, and patients with BSA > 3% at week 16 (n indicates the number of patients with available data for each study visit). [Diagram 5] Proportion of patients achieving PASI75, PASI90, and PASI100 responses among all patients at Weeks 16, 20, and 24. [Figure 6] Improvement in quality of life. (A) Proportion of patients achieving a DLQI of 0 or 1, and (B) Mean DLQI at different time points for all patients, patients with BSA ≤ 3% at week 16, and patients with BSA > 3% at week 16 (n indicates the number of patients with available data for each study visit). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The foregoing aspects and embodiments, as well as other aspects, objects, features and advantages of the present invention will become apparent from the following detailed description. Detailed Description of the Invention

[0031] In a cohort study, nearly half of patients did not achieve BSA 3% with tildrakizumab monotherapy at week 16. Therefore, there is a need for the development of new therapies, either with adjuvant therapy or with switching to a new therapy. In the present invention, the proportion of all patients who achieved BSA 3% or less and PASI 75 increases after only 4 weeks of additional halcinonide ointment, which is applied to those who do not achieve an adequate response to tildrakizumab alone. All disease activity outcomes and patient quality of life are improved with tildrakizumab monotherapy and further improved with the addition of halcinonide ointment. Importantly, the improvement is maintained for 4 weeks after halcinonide ointment is stopped. Furthermore, tildrakizumab alone or in combination with halcinonide ointment is well tolerated and no SAEs are observed.

[0032] Thus, there is provided a method for treating patients suffering from moderate to severe plaque psoriasis, the method comprising the steps of: a) selecting patients with a PASI score of 12 or greater, a body surface area (BSA) affected by psoriasis of 10% or greater, and / or a PGA score of 3 or greater; b) administering to said patients an IL-23 antagonist, preferably tildrakizumab, at a dose of about 100 milligrams by subcutaneous injection at weeks 0, 4, and 16; and c) at week 16, patients with a BSA of greater than 3% apply halcinonide twice daily for 4 weeks, then continue without halcinonide for a further 4-week follow-up period, during which changes from baseline in BSA, PGA, PGAxBSA, PSAI, and DLQI are described. a. Patients receiving halcinonide achieve a BSA level of 1% to 3% at Week 20; b. The percent reduction from baseline in mean BSA, PGA, and PGA x BSA was significantly increased at week 20 after 4 weeks of adjunctive halcinonide therapy; c. The percent reduction from baseline in PSAI (75, 90, and 100) was significantly increased at week 20 after 4 weeks of adjunctive halcinonide therapy; d. The decrease from baseline in DLQI was significantly increased at week 20 after 4 weeks of adjunctive halcinonide therapy; e. A method is provided wherein the response is maintained at 24 weeks after halcinonide ointment has been discontinued for 4 weeks.

[0033] In another embodiment, a method is provided for treating a psoriasis patient receiving an IL-23 antagonist comprising continuing treatment with the IL-23 antagonist, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing a corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the percentage of patients achieving a BSA 3% or less and a PASI (75, 90, or 100) is increased after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to the IL-23 antagonist alone, and said improvement is maintained four weeks after corticosteroid treatment is stopped.

[0034] The following definitions used herein shall apply unless otherwise specified. For example, the term "IL-23 antagonist or inhibitor" targets a type of cytokine called IL-23, which plays a role in the signaling pathway that induces inflammation. IL-23 inhibitors block the action of IL-23, which may help limit the inflammation that causes psoriasis symptoms. IL-23 inhibitors may help reduce the amount of skin affected by psoriasis and also relieve symptoms such as itching, pain, and skin tightness. The FDA has approved three IL-23 inhibitors for the treatment of moderate to severe psoriasis in adults. These are guselkumab (TREMFYA), risankizumab-rzaa (SKYRIZI), and tildrakizumab-asmn (ILUMYA).

[0035] Guselkumab, an interleukin-23 blocker, is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. Guselkumab is produced in a mammalian cell line using recombinant DNA technology. TREMFYA injection is a sterile, preservative-free, clear, colorless to pale yellow solution that may contain small translucent particles. Each single-dose prefilled syringe for subcutaneous use contains 100 mg of guselkumab in 1 mL. TREMFYA is supplied as a single-dose solution in a 1 mL glass syringe with a 27G, half-inch fixed needle assembled into a passive needle guard delivery system. The standard dose is one injection at the start of treatment, one injection at the fourth week of treatment, and one injection every eight weeks thereafter. Each TREMFYA prefilled syringe delivers 1 mL of solution containing guselkumab (100 mg), L-histidine (0.6 mg), L-histidine monohydrochloride monohydrate (1.5 mg), polysorbate 80 (0.5 mg), sucrose (79 mg), and water for injection at pH 5.8.

[0036] In another embodiment, a method is provided for treating a psoriasis patient receiving guselkumab comprising continuing treatment with guselkumab, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing a corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the proportion of patients achieving a BSA 3% or less and a PASI (75, 90, or 100) increases after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to guselkumab alone, and said improvement is maintained four weeks after corticosteroid treatment is stopped.

[0037] Risankizumab-rzaa, an interleukin-23 antagonist, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody. Risankizumab-rzaa is produced in a mammalian cell line using recombinant DNA technology. SKYRIZI (risankizumab-rzaa) injection is a sterile, preservative-free, colorless to slightly yellow, and clear to slightly opalescent solution for subcutaneous use. Each prefilled syringe delivers 0.83 mL, containing 75 mg of risankizumab-rzaa, disodium succinate hexahydrate (0.88 mg), polysorbate 20 (0.17 mg), sorbitol (34 mg), succinic acid (0.049 mg), and water for injection USP.

[0038] In yet another embodiment, a method is provided for treating a psoriasis patient receiving risankizumab comprising continuing treatment with risankizumab, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing a corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the percentage of patients achieving a BSA 3% or less and a PASI (75, 90, or 100) increases after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to risankizumab alone, and said improvement is maintained four weeks after corticosteroid treatment is stopped.

[0039] Tildrakizumab-asmn, a humanized IgG1 / k antibody, specifically binds to the p19 subunit of interleukin-23 (IL-23). ​​Tildrakizumab-asmn is produced in a recombinant Chinese hamster ovary (CHO) cell line and has an approximate molecular weight of 147 kilodaltons. ILUMYA (tildrakizumab-asmn) Injection is a sterile, clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous use. ILUMYA is supplied in a single-dose prefilled syringe with a glass barrel and a fixed 1 / 2 inch 29 gauge needle. The syringe is fitted with a passive needle guard and needle cover. Each 1 mL single-dose prefilled syringe contains 100 mg of tildrakizumab-asmn, formulated in L-histidine (0.495 mg), L-histidine hydrochloride monohydrate (1.42 mg), polysorbate 80 (0.5 mg), sucrose (70.0 mg), and water for injection USP, pH 5.7-6.3.

[0040] In certain embodiments, the invention provides a method for treating a psoriasis patient receiving tildrakizumab comprising continuing treatment with tildrakizumab, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing a corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the proportion of patients achieving a BSA 3% or less and a PASI (75, 90, or 100) increases after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to tildrakizumab alone, and said improvement is maintained four weeks after corticosteroid treatment is stopped.

[0041] The term "corticosteroids" refers to a group of hormones secreted by the adrenal cortex and their analogs. "Corticosteroids" encompass glucocorticoids, mineralocorticoids such as aldosterone, and sex steroids. Glucocorticoids, typified by cortisol, bind to glucocorticoid receptors and have anti-inflammatory, metabolic, and immunomodulatory effects, regulating key homeostatic functions. Some corticosteroids, such as cortisone, have both glucocorticoid and mineralocorticoid effects, while other corticosteroids have primarily glucocorticoid effects.

[0042] A "topical preparation containing a corticosteroid" may be in the form of an ointment, powder, gel ointment, emollient, cream, adhesive patch or strip, shampoo, spray, foam, gel, or liquid.

[0043] Examples of corticostreoids include, but are not limited to, beclomethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clobetasol propionate, clocortolone acetate, clocortolone pivalate, corticosterone, cortisone, ethoximethasone acetate fluocinolone acetonide, halcinonide, halobetasol propionate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone phosphate, hydrocortisone sodium succinate, methylprednisolone acetate (or disodium phosphate, sodium succinate, or aceponate), prednisolone, halcinonide, or prednisone.

[0044] As used herein, the term "halcinonide" refers to HALOG, chemically designated as 21-chloro-9-fluoro-11β,16α,17-trihydroxypregn-4-ene-3,20-dione cyclic 16,17-acetal with acetone. Each gram of 0.1% HALOG (Halcinonide Cream, USP) contains 1 mg of halcinonide in a specially formulated cream base consisting of cetyl alcohol, dimethicone 350, glyceryl monostearate NF XII, isopropyl palmitate, polysorbate 60, propylene glycol, purified water, and titanium dioxide.

[0045] Each mL of 0.1% HALOG solution (halcinonide topical solution, USP) contains 1 mg of halcinonide, edetate disodium, polyethylene glycol 300, and purified water, with butylated hydroxytoluene as an antioxidant.

[0046] Each gram of 0.1% HALOG Ointment (halcinonide ointment, USP) contains 1 mg of halcinonide in Plastibase® (Plasticized Hydrocarbon Gel), mineral oil and a polyethylene gel base, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1450, and polyethylene glycol 6000 distearate, and butylated hydroxytoluene as an antioxidant.

[0047] As used herein, the term "about" refers to any value that is within a range defined by up to ±15% variation of the value.

[0048] The present invention is illustrated below by reference to the following examples, however, those skilled in the art will appreciate that numerous variations, modifications, applications, and extensions of these embodiments and principles may be made without departing from the spirit and scope of the invention, and that the specific methods and results discussed are merely illustrative of the invention.

[0049] Example 1

[0050] A prospective, open-label study evaluating the efficacy and safety of tildrakizumab plus topical halcinonide ointment in patients with psoriasis.

[0051] method

[0052] Study design and participants

[0053] This was a single-center, prospective, open-label study to evaluate the efficacy and safety of tildrakizumab (ILUMYA® [tildrakizumab-asmn] in combination with halcinonide ointment (HALOG® Ointment [halcinonide ointment], USP, 0.1%) for treating moderate to severe plaque psoriasis. The study protocol was approved by the Institutional Review Board and the study was conducted in accordance with ethical guidelines. Written informed consent was obtained by all patients before starting treatment.

[0054] Adults (≥18 years) with chronic, moderate to severe plaque-type psoriasis (BSA ≥10%, Physician's Global Assessment [PGA] ≥3, and Psoriasis Area Severity Index [PASI] ≥12) who were candidates for phototherapy and / or systemic therapy were recruited. Exclusion criteria included active non-plaque type of psoriasis, laboratory abnormalities or medical conditions that could affect patient safety during the study, active or untreated latent tuberculosis, previous or concurrent malignancy, hepatitis B, phototherapy with UVB or PUVA, recent treatment of psoriasis with oral systemic agents, biologics, or topical therapies, recent use of antibiotics or any investigational drug, pregnancy or lactation, and hypersensitivity to the excipients of the investigational drug. Patients who had received a live vaccine within 4 weeks prior to baseline or who planned to receive a live vaccine during the study were also excluded.

[0055] Investigational Drug

[0056] All enrolled patients received tildrakizumab (100 mg) by subcutaneous injection at weeks 0, 4, and 16. Patients with BSA >3% at week 16 applied halcinonide ointment twice daily for 4 weeks and then continued without halcinonide for an additional 4-week follow-up period. Patients with BSA ≤3% at week 16 were also followed up through week 24. All patients were evaluated for safety and efficacy at weeks 4, 8, 16, 20, and 24.

[0057] Test results

[0058] The primary endpoint of the study was the proportion of patients with a BSA 3% or less at week 16. Secondary endpoints included reductions in PASI scores of 75%, 90%, and 100% (PASI75, PASI90, and PASI100, respectively) from baseline at weeks 16, 20, and 24, in addition to the proportion of patients with a BSA 1% or less, a Dermatology Life Quality Index (DLQI) of 0 or 1, and the proportion of patients with a BSA 3% or less at weeks 20 and 24. Improvements in PGA, composite PGA x BSA scale, and DLQI were also assessed as secondary endpoints. Safety outcomes included adverse events (AEs) and serious adverse events (SAEs).

[0059] statistical analysis

[0060] A cohort of approximately 25 participants was planned for enrollment in the study. Changes from baseline in BSA, PGA, PGA x BSA, PASI, and DLQI were summarized descriptively at weeks 4, 8, 16, 20, and 24. Given the sample size, formal statistical analyses were not performed. AEs and SAEs were summarized descriptively by frequency and severity, and their causal relationship to treatment was assessed.

[0061] result

[0062] Patient status and demographic characteristics

[0063] A total of 25 patients were enrolled, 19 completed the study, 1 discontinued due to lack of response to treatment, and 5 were lost to follow-up.

[0064] The majority of patients were male (68%) and Caucasian (76%), and the mean age was 52.6 years. Patients had psoriasis for a mean of 18.9 years. The mean baseline BSA was 19.1%, with mean baseline scores of 3.5 on the PGA, 16.7 on the PASI, and 16.5 on the DLQI. At week 16, 12 patients had a BSA of 3% or less and 11 had a BSA of >3% and received additional halcinonide ointment for 4 weeks.

[0065] BSA and PGA responses

[0066] With tildrakizumab, the percentage of all patients who achieved a BSA of 3% or less was 52.2% at week 16. This percentage for all patients (both 3% or less and >3% BSA at week 16) increased to 73.7% at week 20 (after 4 weeks of additional halcinonide ointment was applied in patients with an unsatisfactory response at week 16) and reached 84.2% at week 24 after patients were off halcinonide ointment for 4 weeks (Figure 1A). In patients who added halcinonide therapy at week 16, 4 achieved a BSA of 3% or less at week 20 and maintained their response level through week 24, 1 achieved a BSA of 3% or less at week 20 but lost response at week 24 (BSA 6%), and 1 achieved a BSA of 3% or less at week 24, resulting in a total of 62.5% of this group achieving a BSA of 3% or less at the end of the study (Figure 1B). Most patients who had a BSA 3% or less at week 16 (without halcinonide) and completed the study maintained a BSA 3% or less at weeks 20 and 24. One patient's BSA increased to 4% at week 20, but dropped again to 3% at week 24. The proportion of all patients with a BSA 1% or less also increased from 21.7% at week 16 to 42.1% at week 20 and 36.8% at week 24 (Figure 1A). In patients using halcinonide, 22.2% achieved a BSA 1% or less at week 20 and 12.5% ​​at week 24 (Figure 1B).

[0067] The mean BSA involvement of all patients decreased from 19.1% at baseline to 5.0% at week 16 (74% decrease), to 2.6% at week 20, and to 2.7% at week 24 (both 86% decrease) (Figure 2). The mean PGA and PGA x BSA of all patients also improved with treatment. In patients with a BSA >3% at week 16, the reductions from baseline in mean BSA, PGA, and PGA x BSA were 55%, 29%, and 64%, respectively, at week 16 and 78%, 51%, and 88%, respectively, at week 20 after 4 weeks of adjunctive halcinonide therapy, and these responses were maintained at week 24 after halcinonide ointment was discontinued for 4 weeks. In patients who had a BSA 3% or less at week 16 and were not using halcinonide, mean BSA, PGA, and PGA × BSA scores decreased by 89%, 60%, and 95%, respectively, from baseline to week 16, and responses were maintained through week 24 (Figures 2-4).

[0068] PASI Response

[0069] In response to tildrakizumab monotherapy, 60.9% of all patients achieved PASI75 (≥75% reduction in PASI score compared to baseline) at week 16, a percentage that increased to 73.7% at weeks 20 and 24. The percentage of all patients achieving PASI90 also increased from 17.4% at week 16 to 52.6% at week 24. PASI100 (complete resolution) was achieved by 4.3% of all patients at week 16 and 21.1% at week 20, but this percentage decreased to 5.3% 4 weeks after halcinonide therapy was stopped (Figure 5).

[0070] Quality of life

[0071] During 16 weeks of tildrakizumab monotherapy, the proportion of all patients reporting a DLQI score of 0 or 1 increased from 4.0% at baseline to 39.2% at week 16, continued to increase (42.1%) at week 20, but decreased to 31.6% at week 24 (Figure 6A).

[0072] The mean DLQI for all patients decreased by 68% from baseline to week 16, and improvement was maintained through week 24. In patients with BSA >3% and who used additional halcinonide ointment, the decrease in mean DLQI from baseline increased from 50% at week 16, to 65% at week 20, and to 61% at week 24. In patients with BSA ≤3% at week 16 who did not use halcinonide ointment, the mean DLQI improved by 84% from baseline to week 16 and remained at similar levels at weeks 20 and 24 (Figure 6B).

Claims

1. 1. A method for treating a patient suffering from moderate to severe plaque psoriasis, said method comprising: PASI score of 12 or more; 10% or more of the body surface area (BSA) affected by psoriasis, and / or selecting patients having a PGA score of 3 or greater; administering to said patient an IL-23 inhibitor at a dose of about 100 milligrams by subcutaneous injection at weeks 0, 4, and 16; At week 16, administering a corticosteroid twice daily for four weeks to said patients with a BSA greater than 3%, followed by an additional four weeks of follow-up without said corticosteroid; and describing the changes from baseline in BSA, PGA, PGAxBSA, PSAI, and DLQI, wherein the patient receiving the corticosteroid achieves a BSA of 1% or less to 3% or less at week 20 and maintains that level of response through week 24.

2. 2. The method of claim 1, wherein the percent reduction from baseline in mean BSA, PGA, and PGA x BSA is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and the response is maintained at 24 weeks after corticosteroid therapy has been discontinued for 4 weeks.

3. 2. The method of claim 1, wherein the percent reduction from baseline in PSAI (75, 90, and 100) is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and the response is maintained at 24 weeks after corticosteroid therapy has been discontinued for 4 weeks.

4. 2. The method of claim 1, wherein the decrease from baseline in DLQI is significantly increased at week 20 after 4 weeks of adjunctive corticosteroid therapy, and the response is maintained at week 24, after corticosteroid therapy has been stopped for 4 weeks.

5. 10. The method of claim 1, wherein the corticosteroid is administered as a topical preparation.

6. 6. The method of claim 5, wherein the topical preparation is in the form of an ointment, powder, gel ointment, emollient, cream, adhesive patch or strip, shampoo, spray, foam, gel, liquid, or solution.

7. 6. The method of claim 5, wherein the corticosteroid is administered as an ointment.

8. 8. The method of any one of claims 1 to 7, wherein the corticosteroid is selected from beclomethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clobetasol propionate, clocortolone acetate, clocortolone pivalate, corticosterone, cortisone, ethoximethasone acetate fluocinolone acetonide, halcinonide, halobetasol propionate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone phosphate, hydrocortisone sodium succinate, methylprednisolone acetate, prednisolone, or prednisone.

9. 2. The method of claim 1, wherein the IL-23 inhibitor is selected from guselkumab, risankizumab, or tildrakizumab.

10. The method of claim 1 , wherein the IL-23 antagonist is tildrakizumab.

11. 16. A method for treating a psoriasis patient receiving an IL-23 antagonist comprising continuing treatment with the IL-23 antagonist, comprising initiating treatment with a topical preparation containing a corticosteroid, continuing treatment with the topical preparation containing the corticosteroid for up to four weeks, and then discontinuing treatment with the topical preparation, wherein the percentage of the patients achieving a BSA of 3% or less increases after only four weeks of applying additional corticosteroid to those who did not achieve an adequate response to the IL-23 antagonist alone, and the improvement is maintained four weeks after corticosteroid treatment is stopped.

12. 12. The method of claim 11, wherein the percent reduction from baseline in mean BSA, PGA, and PGA x BSA is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, the percent reduction from baseline in PSAI (75, 90, and 100) is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and the percent reduction from baseline in DLQI is significantly increased at 20 weeks after 4 weeks of adjunctive corticosteroid therapy, and said response is maintained at 24 weeks after corticosteroid therapy is stopped for 4 weeks.

13. The method of claim 11 , wherein the patient continues said treatment with said IL-23 antagonist for at least about 16 weeks.

14. 12. The method of claim 11, wherein the IL-23 antagonist is guselkumab, risankizumab, or tildrakizumab.

15. The method of claim 11, wherein the IL-23 antagonist is tildrakizumab.

16. 12. The method of claim 11, wherein the corticosteroid is administered as a topical preparation.

17. 17. The method of claim 16, wherein the topical preparation is in the form of an ointment, powder, gel ointment, emollient, cream, adhesive patch or strip, shampoo, spray, foam, gel, liquid, or solution.

18. 12. The method of claim 11, wherein the corticosteroid is selected from beclomethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clobetasol propionate, clocortolone acetate, clocortolone pivalate, corticosterone, cortisone, ethoximethasone acetate fluocinolone acetonide, halcinonide, halobetasol propionate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone phosphate, hydrocortisone sodium succinate, methylprednisolone acetate, prednisolone, prednisone, or halcinonide.

19. The method of any one of claims 16 to 18, wherein the corticosteroid is halcinonide ointment.

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