Pharmaceutical compositions comprising A3 adenosine receptor agonists for treatment of psoriasis

Abstract

The present invention relates to methods and pharmaceutical compositions for the treatment of psoriasis comprising, as an active ingredient, piridipine (IB-MECA) in an amount suitable for administration at a daily dose of about 6 mg (mg).

Description

Technical Field

[0001] The present invention relates to the use of piclidenoson to treat psoriasis, particularly plaque psoriasis. Background Art

[0002] Psoriasis is a common chronic disease that causes skin inflammation, which affects the patient's quality of life, and patients often experience attacks and remissions throughout their lives. Psoriasis is an autoimmune inflammatory disease in which skin plaques are formed due to the resistance of skin keratinocytes to apoptosis. Cytokines including TNF-α, IL-17 and IL-23 induce the continued proliferation of keratinocytes, thereby playing a key role in the pathogenesis of the disease [see Zhou et al. Cell Death Dis 13, 81 (2022)]. Although biological therapies targeting these inflammatory cytokines have been successfully used in the treatment of psoriasis over the past 20 years, their toxicity / side effects, loss of efficacy over time, recurrence of the disease after discontinuation of medication, and costs have prompted people to explore new strategies for the treatment of psoriasis [see Al-Janabi, A. & Yiu, ZZN Porriasis (Auckl) 12, 1-14 (2022)].

[0003] A3 adenosine receptor (A3AR) is overexpressed in the skin and peripheral blood mononuclear cells of patients with psoriasis.

[0004] WO 2011 / 027348 discloses a 3 AR agonist CF101 (methyl 1-[N 6 -(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide, IB-MECA) for treating psoriasis at a daily dose of 4 milligrams (mg). Summary of the invention

[0005] In a first aspect, the present invention provides a pharmaceutical composition for treating psoriasis, wherein the pharmaceutical composition comprises 1-[N 6 -(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide (IB-MECA), the amount of the active ingredient is suitable for administration at a daily dose of about 6 milligrams (mg).

[0006] In one embodiment, the therapeutic pharmaceutical composition is in a dosage form suitable for oral administration.

[0007] In one embodiment, the therapeutic pharmaceutical composition is in a dosage form suitable for administration once or twice daily, with a total daily dose of about 6 mg.

[0008] In one embodiment, the pharmaceutical composition for treatment is an oral solid dosage form.

[0009] In one embodiment, the solid dosage form comprises 3 mg IB-MECA and the solid dosage form is administered twice daily.

[0010] In one embodiment, the dosage form is selected from the group consisting of a pill, a tablet, and a capsule.

[0011] In another aspect, the present invention provides IB-MECA for the treatment of psoriasis in an amount suitable to provide a total daily dose of about 6 mg IB-MECA to a subject in need thereof.

[0012] In one embodiment, the daily dose is formulated for administration once or twice daily.

[0013] In one embodiment, the daily dosage is formulated in a form suitable for oral administration.

[0014] In one embodiment, the therapeutic IB-MECA is formulated for administration as a solid dosage form.

[0015] In one embodiment, the solid dosage form is selected from the group consisting of pills, tablets, and capsules.

[0016] In one embodiment, the dosage form is suitable for administering 3 mg of IB-MECA, and the dosage form is administered twice daily.

[0017] In yet another aspect, the present invention provides a kit comprising a pharmaceutical composition of the present invention as described above and instructions for administering the pharmaceutical composition to a subject in need of treatment for psoriasis at a daily dose of about 6 mg of IB-MECA.

[0018] In one embodiment, the pharmaceutical composition comprises 3 mg IB-MECA, and the instructions comprise administering the pharmaceutical composition to the subject twice daily.

[0019] In yet another aspect, the present invention provides a method comprising administering a daily dose of about 6 mg of IB-MECA to a subject in need of treatment for psoriasis, wherein the subject is being treated for psoriasis.

[0020] In one embodiment, IB-MECA is administered to the subject once or twice daily.

[0021] In one embodiment, IB-MECA is administered orally to the subject.

[0022] In one embodiment, IB-MECA is administered in a form selected from the group consisting of a pill, a tablet, and a capsule.

[0023] In one embodiment, the method comprises administering IB-MECA to the subject twice daily, with each administration comprising 3 mg of IB-MECA.

[0024] In one embodiment, the psoriasis is moderate to severe plaque psoriasis.

[0025] In another aspect, the present invention provides a method for treating psoriasis, comprising administering to a patient in need thereof a daily dose of about 6 milligrams (mg) of 1-[N 6 -(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide (IB-MECA) or a pharmaceutical composition comprising IB-MECA.

[0026] In one embodiment, the IB-MECA or the pharmaceutical composition is administered orally.

[0027] In one embodiment, the IB-MECA or the pharmaceutical composition is administered once or twice daily for a total daily dose of about 6 mg.

[0028] In one embodiment, the IB-MECA or the pharmaceutical composition is administered as a solid dosage form comprising 3 mg of IB-MECA, twice daily.

[0029] In one embodiment, the solid dosage form is selected from the group consisting of pills, tablets, and capsules.

[0030] In one embodiment, the psoriasis is moderate to severe plaque psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to better understand the subject matter disclosed herein and to illustrate how it may be implemented in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0032] Figure 1 is a schematic diagram of the clinical study design.

[0033] Figure 2 is a graph showing the proportion of patients achieving PASI 75 by treatment group over time (weeks).

[0034] Figure 3 is a graph showing the proportion of patients reaching PGA2 by treatment group over time (weeks).

[0035] Figure 4 Graph showing the proportion of patients who achieved improvement in Psoriasis Disability Index (PDI) compared with baseline (BL) at Week 32 by study group (Per-Protocol (PP) population).

[0036] Figure 5A-B is a graph showing the change of 2 mg and 3 mg BID of piridoxine over time (weeks) max (A) and AUC (B). Error bars represent SE. DETAILED DESCRIPTION

[0037] The present invention is based on the results of a Phase 3 clinical trial in patients with moderate to severe plaque psoriasis. The efficacy of orally administered piridixon (also referred to herein as CF-101 or IB-MECA) in improving disease symptoms in patients with psoriasis was examined.

[0038] The randomized, placebo- and active-controlled, double-blind Phase 3 trial (also referred to herein as the COMFORT-1 trial) randomized patients (3:3:3:2) to apiradisone 2 mg twice daily (referred to herein as BID), apiradisone 3 mg BID, apremilast 30 mg BID, or placebo. At week 16, patients in the placebo group were re-randomized (1:1:1) to apiradisone 2 mg BID, apiradisone 3 mg BID, or apremilast 30 mg BID. The primary endpoint was the proportion of patients achieving a ≥75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) at week 16 (PASI-75) compared to placebo.

[0039] A total of 529 patients were randomized and received ≥1 dose of pridisone (safety population). The efficacy analysis population for the primary endpoint included 426 patients (pridisone 2 mg BID, 127; pridisone 3 mg BID, 103; apremilast, 118; placebo, 78). The results of the study showed that oral administration of 3 mg doses of IB-MECA twice daily (i.e., a total daily dose of 6 mg) had a significant effect in improving disease manifestations in these patients.

[0040] That is, the 3 mg BID dose met the primary endpoint: PASI 75 rates for piridesone and placebo were 9.7% and 2.6%, respectively, p=0.037. The PASI response of piridesone continued to increase in a linear manner throughout the study. At week 32, analysis of the per-protocol population showed that a greater proportion of patients (51 / 88, 58.0%) in the piridesone 3 mg BID group had improvements from baseline in the Psoriasis Disability Index (PDI) compared with apremilast (59 / 108, 55.1%), and the non-inferiority test tended to be significant (p=0.072). The safety profile of the 3 mg dose of piridesone is excellent and superior to apremilast. Since psoriasis is a chronic disease that requires lifelong treatment in most cases, good safety is of paramount importance. The Phase 3 trial described herein showed clinically meaningful improvements in skin symptoms and quality of life, highlighting the highly favorable therapeutic index of the 3 mg piridesone dose for psoriasis.

[0041] Piradisone is an A3 adenosine receptor agonist (A3AR) small molecule. Without wishing to be bound by theory, it is believed that the mechanism of action of Piradisone involves inhibition of the inflammatory cytokines, interleukins 17 and 23 (IL-17 and IL-23), and induction of apoptosis of patient skin cells, keratinocytes, which are associated with disease pathogenicity.

[0042] In the context of the present disclosure, the term "psoriasis" includes any form of psoriasis, including but not limited to plaque psoriasis; pustular psoriasis (including arthritic psoriasis or psoriatic arthritis); guttate psoriasis; inverse or flexural psoriasis; erythrodermic psoriasis. In addition, in the context of the present invention, when referring to "psoriasis", it is meant to include any degree of psoriasis, including mild, moderate and severe psoriasis. In a specific embodiment, the term "psoriasis" refers to moderate to severe plaque psoriasis. In a specific embodiment, the term "psoriasis" refers to moderate to severe chronic plaque psoriasis.

[0043] As mentioned above, there are many forms of psoriasis, and each form has unique features that allow the dermatologist to visually identify the psoriasis and determine which type or types of psoriasis are present. Sometimes a skin biopsy is done to confirm the diagnosis. The main types of psoriasis include the following:

[0044] -Plaque psoriasis (reddened areas several inches wide covered with silvery scales)

[0045] -Pustular psoriasis (non-infectious pustules on red skin) -Arthritic psoriasis or psoriatic arthritis

[0046] - Guttate psoriasis (tiny red spots on the skin)

[0047] - Inverse or flexural psoriasis (glossy, red patches in skin folds in areas of friction such as the groin, armpits, or under the breasts)

[0048] - Erythrodermic psoriasis (redness and scaling of large areas of skin).

[0049] In the context of the present disclosure, the term "treatment" includes any improvement in one or more objective parameters (i.e., redness, thickness, and scaling of psoriasis lesions) used to assess psoriasis status (severity) in clinical trials. Based on these parameters, several tools for assessing psoriasis treatment effectiveness have been developed. These assessment tools include traditional assessment tools, such as Psoriasis Area and Severity Index (PASI), Doctor's Global Assessment (PGA), and recent assessment tools, such as National Psoriasis Foundation Psoriasis Score (NPF-PS), Physical Static Comprehensive Assessment (PSGA), and Overall Lesion Assessment (OLA) [referring to document SRFeldman and GGKrueger Psoriasis assessment tools in clinicaltrials, Ann Rheum.Dis.64(Suppl.II):ii65-ii68(2005)].

[0050] PASI and PGA are the two most commonly used tools to assess psoriasis activity and track clinical response to treatment. The PASI assessment tool evaluates the degree of erythema, thickness and desquamation of psoriasis plaques and estimates the extent of involvement of each of these elements in four different body parts (head and neck, trunk, upper limbs and lower limbs). The PASI composite score ranges from 0 to 72. The PGA assessment tool is a six-point score that summarizes the overall erythema, desquamation and thickness as well as the expansion of plaques relative to the baseline assessment. The score includes worst, poor (0-24%), general (25-49%), good (50-74%), excellent (75-99%) and clear (100%) [see Alice B Gottlieb et al. The National Psoriasis Foundation Psoriasis Score System versus the Psoriasis Area Severity Index and Physician's Global Assessment: a comparison, Journal of Drugs in Dermatology June 2003].

[0051] In a specific embodiment, the invention relates to treating psoriasis patients whose body surface area (BSA) is affected ≥ 10%, optionally whose PASI score is ≥ 12, static PGA ≥ 3, and who have had psoriasis for ≥ 6 months.

[0052] The present invention provides a pharmaceutical composition for treating psoriasis comprising IB-MECA as an active ingredient, IB-MECA for treatment, and a method for treating psoriasis. The composition, IB-MECA for treatment, and the method for treating psoriasis are characterized in that the active ingredient (i.e., IB-MECA) is administered to achieve a total daily dose of about 6 mg.

[0053] The term "daily dose" should be understood to include the amount of active ingredient (ie, IB-MECA) administered to a subject in need thereof daily. The daily dose may include a single daily administration or multiple daily administrations, provided that the total amount of IB-MECA received by the subject is about 6 mg per day.

[0054] According to the above, the pharmaceutical composition can be formulated for a single daily administration, in which case the amount of IB-MECA in the composition is about 6 mg; or formulated for administration twice a day, in which case the amount of IB-MECA is about 3 mg. Similarly, the composition can be formulated for administration 3 or 4 times a day, in which case the dosage form will contain about 2 mg and 1.5 mg of IB-MECA, respectively.

[0055] In a preferred embodiment, the active ingredient (i.e., IB-MECA) is formulated in a form suitable for oral administration. However, in some embodiments, the composition may be formulated for nasal administration, may be in the form of an inhalation formulation, may be in the form of a suppository, or may even be formulated for parenteral administration.

[0056] In the context of the present invention, oral administration includes any of the following: (a) liquid solutions, such as an effective amount of IB-MECA dissolved in a diluent, such as water, saline or even orange juice; (b) solid and semi-solid forms; (c) powders; (d) suspensions in appropriate liquids; and (e) suitable emulsions. IB-MECA is typically formulated in a dosage form suitable to achieve the desired 6 mg daily dose.

[0057] Liquid forms may include diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyvinyl alcohol, with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifiers.

[0058] Solid forms are preferred administration forms in the context of the present invention and may include, but are not limited to, pills, tablets, including immediate release and sustained release (controlled release) tablets, uncoated and coated tablets (including enteric coatings), chewable tablets, bilayer or multilayer tablets; granules; capsules, including soft gelatin capsules and hard shell gelatin capsules; powders, including granules for reconstitution and oral powders, lozenges, cachets.

[0059] Capsules may include, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablets may include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, cross-linked sodium carboxymethylcellulose, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenges

[0060] This may include IB-MECA in a flavoring such as sucrose and acacia or tragacanth, as well as pastilles comprising IB-MECA in an inert matrix such as gelatin and glycerin or containing in addition to IB-MECA sucrose and acacia, emulsions, gels, and the like as are known in the art.

[0061] The pharmaceutical composition also comprises at least one pharmaceutically acceptable excipient to facilitate oral delivery of IB-MECA.

[0062] In one embodiment, the pharmaceutical composition is in the form of a tablet. Tablets can be prepared by compression or molding with one or more of the optional excipients. Compressed tablets can be prepared by compressing IB-MECA in a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with one or more excipients, such as a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered IB-MECA and any suitable carrier in a suitable machine.

[0063] Those skilled in the art of pharmaceutics and formulation of pharmaceutical ingredients will be able to design an endless variety of formulations for oral or other forms of administration.

[0064] According to the present disclosure, IB-MECA can be administered once, twice, or several times a day. In one embodiment, IB-MECA is administered once a day, and the dosage form includes about 6 mg of IB-MECA. In another embodiment, IB-MECA is administered twice a day, and each administration of the dosage form includes about 3 mg of IB-MECA (to achieve a total daily amount of 6 mg).

[0065] The present disclosure also provides the use of IB-MECA in treating psoriasis or in preparing a pharmaceutical composition for treating psoriasis, wherein the administration dosage is formulated in a form suitable for daily administration of about 6 mg of IB-MECA.

[0066] Finally, the present disclosure provides IB-MECA for use in treating psoriasis, wherein the IB-MECA is administered to a subject suffering from psoriasis at a daily dose of about 6 mg.

[0067] The term "about" should be understood to include dosages within a range of 10% less or 10% more ("±10%") than the indicated dosage.

[0068] Description of non-limiting embodiments

[0069] Materials and methods

[0070] Study Design

[0071] The COMFORT-1 study is a Phase 3, multicenter (study sites are located in Bosnia, Bulgaria, Canada, Israel, Moldova, Poland, Romania, and Serbia), randomized, double-blind, controlled clinical trial (Clinical Trials Government Identifier: NCT03168256) for moderate to severe plaque psoriasis. The trial has 2 phases ( Figure 1 ). The first phase (weeks 0-16) included 4 treatment groups: two groups receiving piridexone (2 mg or 3 mg BID), one group receiving the active control drug apremilast (titrated to a dose of 30 mg BID within 6 days according to the label), and a placebo group. Eligible patients were randomly assigned to these groups in a 3:3:3:2 ratio. Blinding was maintained using a double-dummy technique. The second phase (weeks 16-32) included 3 treatment groups. At week 16, patients in the placebo group were re-randomized in a 1:1:1 ratio to piridexone 2 mg BID, piridexone 3 mg BID, or apremilast (titrated to a dose of 30 mg BID within 6 days) and treated until week 32. Those patients initially assigned to piridexone or apremilast continued to receive the originally assigned treatment until week 32. Blinding continued until week 32. Patients were evaluated for efficacy and safety every two weeks. The primary efficacy endpoint was assessed at Week 16, and secondary endpoints were assessed at Weeks 16 and 32. Pharmacokinetic (PK) sampling was performed at Weeks 0, 8, and 16.

[0072] This study was approved by all relevant national regulatory agencies and local ethics committees / institutional review boards. This study was conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all patients.

[0073] Study Patients

[0074] The study population included male and female patients aged 18-80 years diagnosed with moderate to severe chronic plaque psoriasis with ≥10% body surface area (BSA) involvement who were candidates for systemic therapy or phototherapy. The main inclusion criteria were PASI score ≥12, static PGA ≥3, and psoriasis for ≥6 months. Key exclusion criteria included prior treatment with apremilast within 4 weeks of the baseline (BL) visit, or contraindications to apremilast, certain prior / concomitant treatments within 4 weeks of the BL visit, such as use of systemic retinoids, corticosteroids, tofacitinib, or immunosuppressants; use of approved / investigational biologics for a period equal to 5 times the circulating half-life of the biologic or within 30 days (whichever is longer) before the BL visit; use of high-potency dermatologic corticosteroids (class I-III in the United States and class III-IV in Europe), vitamin D analogs, keratolytics, or coal tar (except on the scalp, palms, groin, and / or soles) within 2 weeks of the BL visit; ultraviolet light / Dead Sea therapy within 4 weeks of the BL visit, or anticipated need for these therapies during the study. Renal or hepatic dysfunction, uncontrolled concomitant illness, and pregnancy / lactation.

[0075] Efficacy and safety evaluation

[0076] The primary endpoint includes the proportion of patients (superiority) and safety of 2mg BID group and 3mg BID group of piridison compared to placebo in PASI 75 at week 16. The secondary endpoints of week 16 compared the piridison group with placebo, including the proportion of patients reaching PASI 50, the proportion of patients reaching a score of 0 or 1 in PGA2 (a measure based on PASI calculated using the intensity grading of each component in the PASI score; specifically, it is the average value of PASI erythema, infiltration and peeling scores) [see Gordon, KBetal.N Engl J Med 373,136-144 (2015)] and the proportion of patients improved compared to BL in the Psoriasis Disability Index (PDI). Other secondary endpoints were evaluated at week 32, and the piridison group was compared with Apremilast. These comparisons include the proportion of patients reaching PASI 75, PASI 50, PGA2 being 0 or 1, and the proportion of patients improved compared to BL in PDI. PK analysis was performed at weeks 0, 8, and 16, including calculation of peak blood concentrations of drug after administration (C max ).

[0077] Safety assessments included treatment-emergent adverse events (TEAEs) and changes in vital signs, physical examinations, clinical laboratory tests (liver, kidney, hematology, chemistry, and urinalysis), and electrocardiogram results.

[0078] Statistical analysis

[0079] Overall, 4 analysis populations were defined: the safety population, including all patients who received ≥1 dose of apiridicon; the intention-to-treat (ITT) population, including all persons in the safety population with at least one PASI score recorded after BL, and excluding patients who withdrew before week 16 due to COVID-19-related study pauses; the modified ITT (mITT) population for week 16 efficacy analysis, including all ITT patients, except for one patient in the placebo group who was excluded due to a major protocol violation not recorded in the original data; and finally, the per-protocol (PP) population for week 32 analysis, including all ITT patients who had no major protocol violations at or before week 16 and completed week 16 of the study. Exclusion from the PP population was completed before any open-label analyses were performed. Analyses performed at week 32 were performed separately for patients initially randomized to apiridicon or apremilast and for patients initially randomized to placebo.

[0080] Descriptive statistics were used to summarize patient characteristics and safety.TEAEs were reported by treatment group for each system organ class (SOC) and preferred term (PT), as defined in the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0. If a patient had more than one TEAE with the same PT, the patient was counted once.

[0081] For efficacy analyses, missing values ​​were imputed. For the primary efficacy analysis, missing values ​​due to discontinuation were considered as nonresponse after discontinuation, which is called nonresponder imputation (NRI); intermediate missing values ​​were imputed using the last observation carried forward (LOCF) method. Missing values ​​for secondary efficacy analyses were also imputed using NRI. The p-values ​​for the primary efficacy analysis comparing piridexamid versus placebo and the p-values ​​for the secondary analyses were determined using the normal approximation (NAB) comparing 2 binomial proportions. The secondary analysis comparing piridexamid versus apremilast was a noninferiority analysis, using a noninferiority margin of 10% using NAB. Data are presented as proportion / mean ± SE.

[0082] All statistical tests were two-sided, and p < 0.05 was considered statistically significant.

[0083] result

[0084] A phase III, multicenter, randomized, placebo- and active-controlled, double-blind study was conducted to evaluate the efficacy and safety of piridoxine (IB-MECA, CF101) in patients with moderate to severe plaque psoriasis.

[0085] patient

[0086] A total of 701 patients with moderate to severe plaque psoriasis were screened. Patients who met the eligibility criteria (N=529) were randomly assigned to piridexa 2 mg BID (N=151), piridexa 3 mg BID (N=142), apremilast (N=142), or placebo (N=94).

[0087] Overall, nearly one-third of patients (n=158, 29.9%) across all treatment groups discontinued treatment during the first phase of the study (weeks 0-16), with the most common reason being COVID-19-related study pauses (n=93, 17.6% across all treatment groups). Other reasons for study discontinuation included patient requests (n=39, 7.4%) and TEAEs (n=7, 1.3%).

[0088] Table 1 shows the baseline patient and disease characteristics of the study safety population by treatment, demonstrating a balanced distribution between study groups. The majority of study patients were male, the median age (range) for the entire study population was 49 (19-81) years, and all but one patient were white. The median (range) disease duration for all patients was 12 (0-67) years and was similar between treatment groups.

[0089] Table 1: Baseline patient and disease characteristics

[0090]

[0091] BID, twice daily; BMI, body mass index

[0092] Efficacy vs. placebo (week 16)

[0093] The primary endpoint of the study was met. At week 16, patients treated with piridex 3 mg in the mITT population demonstrated statistically significant improvements compared to placebo as measured by the Psoriasis Area and Severity Index (PASI) 75 response: piridex 3 mg: 9.7% ± 1.8% vs. placebo: 2.6% ± 1.8% (p = 0.037) ( Figure 2 ).

[0094] Although a higher proportion of patients achieved PASI 75 in the 2 mg BID group compared with placebo at week 16 in the mITT population, the difference was not statistically significant (7.9% ± 2.4% vs. 2.6% ± 1.8%, p = 0.075). For both doses, the proportion of patients improved linearly over time ( Figure 2 ).

[0095] For the secondary endpoint of the proportion of patients achieving PGA2 at week 16 in the mITT population ( Figure 3), the proportion of patients taking piridesone 3 mg BID (10.7% ± 3.0%) and 2 mg BID (11.8% ± 2.8%) was higher than placebo (3.8% ± 2.2%). The difference observed between piridesone 3 mg BID and placebo trended towards statistical significance (p = 0.068), and for the 2 mg BID dose, the difference was significant (p = 0.027).

[0096] Additional secondary endpoints were evaluated in the mITT population at week 16, including the proportion of patients achieving PASI 50 and the proportion of patients with improvement in PDI compared to BL, and no statistically significant superiority of any dose of piridesone was shown over placebo. The proportion of patients who achieved PASI 50 was 19.4% for piridesone 3 mg BID, compared to 15.4% for placebo (p = 0.475). For patients who received piridesone 2 mg BID, this proportion was 26.0%, a difference that tended to be statistically significant compared to placebo (p = 0.060). For 3 mg BID, 2 mg BID, and placebo, the proportion of patients who achieved PDI improvement compared to BL was 58.3%, 63.3%, and 60.3%, respectively (p = 1.00 and p = 0.70, respectively, for each comparison with placebo).

[0097] Efficacy in patients initially randomized to receive active treatment compared with apremilast (week 32)

[0098] At week 32, the noninferiority of piridixone to apremilast was evaluated in the PP population, which included patients initially randomized to receive active treatment. For the proportion of patients achieving PASI 75, noninferiority was not established for piridixone 3 mg BID compared with apremilast (17.0% vs. 26.2%, respectively; p=0.881), whereas noninferiority was established for piridixone 2 mg BID compared with apremilast (20.8% vs. 26.2%, respectively; p=0.429). A lower proportion of patients achieved PASI 50 with both piridixone doses compared with apremilast, and noninferiority was not established (19.3%, 17.0%, and 25.2% for piridixone 3 mg BID, 2 mg BID, and apremilast, respectively; p=0.49 and p=0.75 for the respective comparisons with apremilast, respectively). Similarly, the proportion of patients with a PGA2 of 0 or 1 was also lower compared with apremilast (at both doses), and non-inferiority was not established (15.9%, 18.9%, and 24.3% for piridixone 3 mg BID, 2 mg BID, and apremilast, respectively; p=0.777 and p=0.417 for the comparison with apremilast, respectively).

[0099] A greater proportion of patients in the pridisone 3 mg BID group had an improvement in PDI compared with BL (58.0% vs. 55.1%) compared with apremilast. The non-inferiority test tended to be significant (p = 0.072, Figure 4 The corresponding ratio in 2 mg BID was 48.1%, and non-inferiority compared to apremilast was not established (p=0.66).

[0100] Security

[0101] Throughout the 32-week study period, piridoxine 2 mg BID and piridoxine 3 mg BID were well tolerated, with the higher dose of piridoxine not increasing the frequency of TEAEs (Table 2). The safety profile of both piridoxine doses was generally comparable to placebo, which was used only from Weeks 0 to 16. In addition, the safety profile of piridoxine was more favorable than that of apremilast, which was associated with a higher incidence of neurologic disorders (9.6% for apremilast vs. 1.7% per dose of piridoxine) and a higher incidence of gastrointestinal disorders (7.3% for apremilast vs. 2.8% for piridoxine 2 mg BID and 1.2% for piridoxine 3 mg BID). In the piridoxine group, the only TEAEs that occurred in >2% of patients were nasopharyngitis (2.2% and 2.9% in the 2 mg BID and 3 mg BID groups, respectively) and urinary tract infection (3.4% in the 2 mg BID group) (Table 2). Furthermore, when all patients received active treatment, no cumulative risk of priligy was observed with treatment beyond week 16.

[0102] Overall, there were 3 serious TEAEs in patients receiving effective treatment, including 1 patient receiving 2 mg BID of pirides (arterial embolism), 1 patient receiving 3 mg BID of pirides (osteomyelitis), and 1 patient receiving apremilast (pneumonia); the investigators considered these to be unrelated to the drug. 9 patients withdrew from the study due to 10 TEAEs (7 in weeks 0-16 and 2 in weeks 16-32), including 1 in each of the placebo and apremilast groups, 2 in the 2 mg BID of pirides, and 5 in the 3 mg BID of pirides. The investigators considered all events to be unrelated to the drug. Electrocardiograms showed that the drug had no clinically significant effect on QTcF or other parameters during treatment in all groups. No other noteworthy safety events occurred during the entire study period, and no deaths were reported.

[0103] Table 2: Incidence of TEAEs in the Safety Population from Week 0 to Week 32 a

[0104]

[0105] GI = gastrointestinal, sc = subcutaneous

[0106] a Cases with an incidence >2% in MedRA SOC (system organ class) were included.

[0107] b Included were 151 patients who received priligy 2 mg BID in phase 1 of the study, plus 28 patients who received placebo in phase 1 and were re-randomized to priligy 2 mg BID at week 16.

[0108] c Included were 142 patients who received priligy 3 mg BID in phase 1 of the study, plus 31 patients who received placebo in phase 1 and were re-randomized to priligy 3 mg BID at week 16.

[0109] d The study included 142 patients who received apremilast in phase 1 of the study, plus 35 patients who received placebo in phase 1 and were re-randomized to apremilast at week 16.

[0110] e Patients received placebo-only treatment for 16 weeks before being re-randomized to receive active treatment.

[0111] Pharmacokinetics (PK)

[0112] PK data showed that, if C max Exposure to piridicon, as measured by AUC (area under the curve), was similar in the 2 mg BID and 3 mg BID groups (Figure 5).

Claims

1. A pharmaceutical composition for treating psoriasis, comprising as an active ingredient 1-[N 6 -(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide (IB-MECA), the amount of the active ingredient is suitable for administration at a daily dose of about 6 milligrams (mg).

2. The pharmaceutical composition for treatment according to claim 1, which is in a dosage form suitable for oral administration.

3. The pharmaceutical composition for treatment according to claim 1 or 2, which is in a dosage form suitable for administration once or twice a day, with a total daily dose of about 6 mg. The therapeutic pharmaceutical composition according to claim 1 or 2, which is an oral solid dosage form.

5. The pharmaceutical composition for treatment according to claim 4, wherein the solid dosage form comprises 3 mg IB-MECA, which is administered twice a day.

6. The therapeutic pharmaceutical composition according to any one of claims 1 to 5, wherein the dosage form is selected from pills, tablets and capsules.

7. IB-MECA for the treatment of psoriasis, in an amount suitable to provide a total daily dose of about 6 mg IB-MECA to a subject in need of treatment.

8. The therapeutic IB-MECA according to claim 7, wherein the daily dose is formulated for administration once or twice daily.

9. The therapeutic IB-MECA according to claim 7 or 8, wherein the daily dose is formulated in a form suitable for oral administration.

10. The therapeutic IB-MECA according to claim 9, which is formulated in the form of a solid dosage form for administration.

11. The therapeutic IB-MECA according to claim 10, wherein the solid dosage form is selected from the group consisting of a pill, a tablet and a capsule.

12. The therapeutic IB-MECA according to any one of claims 7 to 11, in a dosage form suitable for administration of 3 mg IB-MECA twice daily.

13. A kit comprising the pharmaceutical composition of any one of claims 1 to 6 and instructions for administering the pharmaceutical composition to a subject in need of treatment for psoriasis at a daily dose of about 6 mg of IB-MECA.

14. The kit of claim 13, wherein the pharmaceutical composition comprises 3 mg IB-MECA and the instructions comprise administering the pharmaceutical composition to the subject twice daily.

15. The therapeutic pharmaceutical composition of any one of claims 1 to 6, or the therapeutic IB-MECA of any one of claims 7 to 12, or the kit of any one of claims 13 or 14, wherein the psoriasis is moderate to severe plaque psoriasis.

16. A method for treating psoriasis comprising administering to a patient in need thereof a daily dose of about 6 milligrams (mg) of 1-[N 6 -(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide (IB-MECA) or a pharmaceutical composition comprising IB-MECA.

17. The method of claim 16, wherein the IB-MECA or the pharmaceutical composition is administered orally.

18. The method of claim 16 or 17, wherein the IB-MECA or the pharmaceutical composition is administered once or twice daily at a total daily dose of about 6 mg.

19. The method of any one of claims 16 to 18, wherein the IB-MECA or the pharmaceutical composition is administered in a solid dosage form comprising 3 mg IB-MECA administered twice daily.

20. The method of claim 19, wherein the solid dosage form is selected from the group consisting of a pill, a tablet, and a capsule.

21. The method of any one of claims 16 to 20, wherein the psoriasis is moderate to severe plaque psoriasis.

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