Pharmaceutical composition containing an A3 adenosine receptor agonist for the treatment of psoriasis

Abstract

The present invention relates to a method and a pharmaceutical composition for use in the treatment of psoriasis, which contain picidenoson (IB-MECA) as an active ingredient in an amount suitable for administration at a daily dose of about 6 milligrams (mg).

Description

Technical Field

[0001] The present invention relates to the treatment of psoriasis, particularly plaque psoriasis, with picrilidenosone.

Background Art

[0002] Psoriasis is a common chronic pathological condition that causes skin inflammation affecting the quality of life of patients, and patients often experience relapses and remissions throughout their lives. Psoriasis is an autoimmune inflammatory disease, and skin plaques are formed due to the resistance of skin keratinocytes to apoptosis. Cytokines including TNF-α, IL-17, and IL-23 induce continuous proliferation of keratinocytes and thereby play a major role in the disease etiology [Zhou et al., Cell Death Dis 13, 81 (2022)]. During the past 20 years, biological therapies targeting these inflammatory cytokines have been well implemented as psoriasis treatments, but their toxicity / side effects, loss of efficacy over time, disease recurrence after their discontinuation, and cost have prompted the search for new strategies for psoriasis treatment [Al-Janabi, A. and Yiu, Z.Z.N. Psoriasis (Auckl) 12, 1-14 (2022)].

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

[0004] WO2011 / 027348 discloses a pharmaceutical composition containing the A3AR agonist CF101 (methyl 1-[N 6 -(3-iodobenzyl)-adenine-9-yl]-β-D-ribofuranamide, IB-MECA) for use in the treatment of psoriasis at a daily dose of 4 milligrams (mg).

Summary of the Invention

[0005] In a first aspect thereof, the present invention provides an active ingredient 1-[N 6Provide a pharmaceutical composition for use in the treatment of psoriasis comprising [-(3-iodobenzyl)-adenin-9-yl]-β-D-ribofuranosylamide (IB-MECA).

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

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

[0008] In one embodiment, the pharmaceutical composition for use is in a solid oral dosage form.

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

[0010] In one embodiment, the dosage form is selected from pills, tablets, and capsules.

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

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

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

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

[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 administration of 3 mg of IB-MECA, which is administered twice a day.

[0017] In another aspect, the present invention provides a package comprising the pharmaceutical composition of the present invention as defined above and instructions for administering this pharmaceutical composition to a subject in need of treating psoriasis with a daily dose of about 6 mg of IB-MECA.

[0018] In one embodiment, the pharmaceutical composition comprises 3 mg of IB-MECA and the instructions include administering the pharmaceutical composition to the subject twice a day.

[0019] In 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 treating psoriasis, wherein the subject is being treated for psoriasis.

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

[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 pills, tablets, and capsules.

[0023] In one embodiment, the method comprises administering IB-MECA to the subject twice a day, and each dosage comprises 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 1-[N to a patient in need thereof at a daily dose of about 6 milligrams (mg). 6A method for the treatment of psoriasis is provided, which comprises administering [[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 a day, and the total daily dose is about 6 mg.

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

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

[0030] In one embodiment, the psoriasis is moderate to severe plaque psoriasis.

[0031] For a better understanding of the subject matter disclosed herein and to exemplify how it may be practiced, embodiments are described herein, by way of non-limiting example only, with reference to the accompanying drawings. **Brief Description of the Drawings**

[0032]

Figure 1

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Figure 3

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DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention is based on the results of a Phase 3 clinical trial in patients suffering from moderate - to - severe plaque psoriasis. The efficacy of oral administration of picrilodine (also called CF - 101 or IB - MECA herein) in improving the disease symptoms of psoriasis patients was tested.

[0034] In a randomized, placebo - and active - comparator, double - blind Phase 3 trial (also called the COMFORT - 1 trial herein), patients were randomized (3:3:3:2) to twice - daily (denoted as BID herein) picrilodine 2 mg, picrilodine 3 mg BID, apremilast 30 mg BID, or placebo. At week 16, patients in the placebo group were re - randomized (1:1:1) to picrilodine 2 mg BID, picrilodine 3 mg BID, or apremilast 30 mg BID. The primary endpoint was the proportion of patients who achieved at least a 75% improvement in the Psoriasis Area and Severity Index (PASI) from baseline (PASI - 75) by the affected body surface area compared to placebo at week 16.

[0035] A total of 529 patients were randomized and received at least one dose of picrilodine (safety analysis set). The efficacy analysis set for the primary endpoint included 426 patients (picrilodine 2 mg BID, 127 patients; picrilodine 3 mg BID, 103 patients; apremilast, 118 patients; placebo, 78 patients). The trial results showed a significant effect of the 3 mg dose of IB - MECA (i.e., a total daily dose of 6 mg) administered orally twice a day in improving the disease signs in these patients.

[0036] That is, the primary efficacy endpoints were met at the 3 mg BID dose: 9.7% vs. 2.6% PASI 75 rates for picrilodine vs. placebo, p = 0.037. The PASI response with picrilodine continued to increase linearly throughout the study period. At Week 32, analysis of the per-protocol population showed that a greater proportion of patients in the picrilodine 3 mg BID group (51 / 88, 58.0%) achieved improvement from baseline on the psoriasis-specific quality of life assessment measure (PDI) compared to apremilast (59 / 108, 55.1%), and the test for non-inferiority was trending significantly closer (p = 0.072). The safety profile of picrilodine at the 3 mg dose was excellent and better than apremilast. Since psoriasis is a chronic disease that most often requires lifelong treatment, a favorable safety profile is of utmost importance. The clinically important improvements demonstrated in the Phase 3 trials described herein clearly show a very favorable treatment index for the 3 mg picrilodine dose in psoriasis, in both skin symptoms and quality of life.

[0037] Picrilodine is a small molecule that is an A3 adenosine receptor (A3AR) agonist. Without being bound by any particular theory, the mechanism of action of picrilodine necessarily involves inhibition of the inflammatory cytokines interleukin 17 and 23 (IL-17 and IL-23) and induction of apoptosis in the skin cell keratinocytes of patients involved in disease pathogenicity.

[0038] As used in connection with the present disclosure, the term "psoriasis" includes all types of psoriasis, including plaque psoriasis; pustular psoriasis (including arthropathic psoriasis or psoriatic arthritis); guttate psoriasis; inverse psoriasis or flexural psoriasis; erythrodermic psoriasis, but is not limited thereto. Further, in connection with the present invention, when reference is made to "psoriasis", it is intended to include all degrees of psoriasis, including mild, moderate, and severe psoriasis. In a particular embodiment, the term "psoriasis" refers to moderate to severe plaque psoriasis. In a particular embodiment, the term "psoriasis" refers to moderate to severe chronic plaque psoriasis.

[0039] As described above, there are multiple types of psoriasis, and each type has unique characteristics that enable a dermatologist to visually distinguish psoriasis to determine which type(s) of psoriasis is present. A skin biopsy may also be performed to confirm the diagnosis. The major types of psoriasis include the following: · Plaque psoriasis (erythematous areas several inches in diameter covered by silver scales) · Pustular psoriasis (non-infectious pustular blisters on erythematous skin) · Psoriatic arthritis · Guttate psoriasis (small red spots on the skin) · Inverse psoriasis or flexural psoriasis (shiny erythema in areas of friction such as in the groin, in the axillae or under the breasts) · Psoriatic erythroderma (erythema and desquamation of most of the skin).

[0040] As used in connection with the present disclosure, the term "treatment" includes improvement in one or more subject parameters used to evaluate the psoriasis condition (severity), i.e., the erythema, thickness, and scaling of psoriasis lesions, in clinical trials. Based on these parameters, multiple tools have been developed to evaluate the effectiveness of psoriasis treatment. The evaluation tools include conventional evaluation tools such as the Psoriasis Area and Severity Index (PASI) by affected site area, the Physician's Global Assessment (PGA), as well as more recent evaluation tools such as the National Psoriasis Foundation - Psoriasis Score (NPF - PS), the Physician Static Global Assessment (PSGA), and the Overall Lesion Assessment (OLA) [S.R. Feldman and G.G. Krueger, Psoriasis assessment tools in clinical trials, Ann Rheum. Dis. 64 (Suppl. II): ii65 - ii68 (2005)].

[0041] PASI and PGA are the two most widely used tools in assessing the activity of psoriasis and in tracking clinical response to treatment. The PASI assessment tool evaluates the erythema, thickness, and scaling of psoriatic plaques and estimates the degree of involvement of each of these factors at four different body sites (head, trunk, upper extremities, and lower extremities). The PASI composite score ranges from 0 to 72. The PGA assessment tool is a six-point scale that summarizes the overall erythema, scaling, and thickness, as well as the spread of plaques, compared to the baseline assessment. The scores include worsening, poor (0 - 24%), moderate (25 - 49%), good (50 - 74%), very good (75 - 99%), and asymptomatic (100%) [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].

[0042] In certain embodiments, the invention relates to the treatment of psoriasis patients having an affected body surface area (BSA) ≧ 10%, optionally a PASI score ≧ 12, a static PGA ≧ 3, and having psoriasis for more than six months.

[0043] The invention provides a pharmaceutical composition comprising IB-MECA as an active ingredient for use in treating psoriasis, the use of IB-MECA for use in treatment, and a method for treating psoriasis, wherein the composition, the use of IB-MECA, and the method are characterized in that the active ingredient, namely IB-MECA, is administered such that a total daily dose of about 6 mg is achieved.

[0044] The term "daily dose" is to be understood as including the amount of the active ingredient, i.e., IB-MECA, administered per day to the subject in need thereof. When the total amount of IB-MECA received by the subject per day is about 6 mg, the daily dose may include a single daily administration or multiple administrations per day, i.e., two or more times a day.

[0045] In accordance with the above, the pharmaceutical composition may be formulated for single daily administration, in which case the amount of IB-MECA in the composition is about 6 mg, or may be formulated for twice-daily administration, in which case the amount of IB-MECA is about 3 mg. Similarly, the composition may be formulated for three or four daily administrations, in which case the dosage forms contain about 2 and 1.5 mg of IB-MECA, respectively.

[0046] In a preferred embodiment, the active ingredient, i.e., IB-MECA, may be formulated in a form suitable for oral administration. However, in some embodiments, the composition may be formulated for nasal administration, may be formulated in the form of an inhalation preparation, may be formulated in the form of a suppository, or may be further formulated for parenteral administration.

[0047] Oral administration, in the context of the present invention, includes any one of: (a) a solution, such as an effective amount of IB-MECA dissolved in a diluent such as water, saline, or orange juice; (b) solid and semi-solid forms; (c) powders; (d) suspensions in a suitable liquid; and (e) suitable emulsions. IB-MECA is typically formulated in a dosage form suitable to achieve the desired daily dose of 6 mg.

[0048] The liquid form may include diluents such as water and alcohols, such as ethanol, benzyl alcohol, and polyethylene alcohols, and may or may not have added thereto a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.

[0049] Solid forms, which are preferred dosage forms in relation to the present invention, include pills, tablets (including immediate-release tablets and controlled-release tablets), uncoated tablets and coated tablets (including enteric coating agents), chewable tablets, two-layer tablets or multi-layer tablets; pellets; capsules (including soft gelatin gel capsules and hard gelatin capsules); powders (including granules) and oral powders for reconstitution, lozenges, cachets, and the like, but are not limited thereto.

[0050] Capsules may contain, for example, surfactants, lubricants, and inert fillers (such as lactose, sucrose, calcium phosphate, and corn starch). Tablets may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other additives, coloring agents, diluents, buffering agents, disintegrants, wetting agents, preservatives, flavoring agents, and pharmaceutically compatible carriers. Lozenges may contain IB-MECA in a flavoring (such as sucrose and acacia or tragacanth), or may be pastille lozenges containing IB-MECA in an inert base (such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, etc.) (including those containing carriers known in the art in addition to IB-MECA).

[0051] The pharmaceutical composition further contains at least one pharmaceutically acceptable additive that facilitates the oral delivery of IB-MECA.

[0052] In one embodiment, the pharmaceutical composition is in the form of tablets. The tablets may be prepared by compression or molding, optionally together with one or more of the above additives. Compressed tablets may optionally be mixed with additives such as binders, lubricants, inert diluents, surfactants or dispersants, and IB-MECA in a free-flowing form, such as powder or granules, may be compressed in a suitable apparatus. Molded tablets may be prepared by molding a mixture of powdered IB-MECA and any suitable carrier in a suitable apparatus.

[0053] Those skilled in the art of pharmacy and pharmaceutical technology of pharmaceutical components would be able to devise innumerable different formulations for oral administration or other dosage forms.

[0054] In accordance with the present disclosure, IB-MECA may be administered once, twice, or multiple times per day. In one embodiment, IB-MECA is administered once a day, and the dosage form contains about 6 mg of IB-MECA. In another embodiment, IB-MECA is administered twice a day, and each dosage form contains about 3 mg of IB-MECA (so as to reach a total daily dose of 6 mg).

[0055] The present disclosure also provides the use of IB-MECA in the treatment or in the preparation of a pharmaceutical composition for the treatment of psoriasis, and the dosage is formulated in a form suitable for the daily administration of about 6 mg of IB-MECA.

[0056] Finally, the present disclosure provides IB-MECA for use in the treatment of psoriasis, and IB-MECA is administered to a subject having psoriasis at a daily dose of about 6 mg.

[0057] The term "about" is to be understood to include dosages that are within 10% less or 10% more of the indicated dosage ("±10%").

[0058] Description of Non-limiting Examples Materials and Methods Test Design The COMFORT-1 trial was a Phase 3, multicenter, randomized, double-blind, comparative clinical trial in moderate to severe plaque psoriasis at sites in Bosnia, Bulgaria, Canada, Israel, Moldova, Poland, Romania, and Serbia (ClinicalTrials.gov identifier: NCT03168256). The trial had two segments (Figure 1). The first segment (weeks 0 to 16) included four treatment groups: two groups with picrolimus (2 mg or 3 mg BID); one group with apremilast as the active comparator (dose escalated to 30 mg BID over 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 the double-dummy technique. The second segment (weeks 16 to 32) included three treatment groups. At week 16, patients from the placebo group above were randomly re-assigned at a 1:1:1 ratio to picrolimus 2 mg BID, picrolimus 3 mg BID, or apremilast (dose escalated to 30 mg BID over 6 days) and treated until week 32. Patients originally assigned to picrolimus or apremilast remained on their initially assigned treatment until week 32. Blinding was maintained until week 32. Patients were evaluated every 2 weeks for efficacy and safety. The primary efficacy analysis assessment item was evaluated at week 16, and the secondary assessment items were evaluated at weeks 16 and 32. Pharmacokinetic (PK) sampling was performed at weeks 0, 8, and 16.

[0059] The above trial was approved by all relevant national regulatory authorities and local ethics committees / institutional review boards. The above trial was conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all patients.

[0060] Subject patients The test population included male and female patients aged 18 to 80 years who were diagnosed with moderate to severe chronic plaque psoriasis, had lesions on ≧10% of the body surface area (BSA), and were candidates for systemic treatment or phototherapy. The main criteria for trial subjects were having a PASI score ≧12, a static PGA ≧3, and having psoriasis for ≧6 months. The main exclusion criteria for the clinical trial were pre-treatment with apremilast within 4 weeks of baseline (BL) visit, or contraindication to apremilast, specific pre-treatments / combination treatments such as systemic administration of retinoids, corticosteroids, tofacitinib, or immunosuppressants within 4 weeks of BL visit; an approved / investigational biologic agent within a period equal to 5 times the circulating half-life of the agent, or within a period of 30 days prior to BL visit (whichever is longer); high-potency dermatologic corticosteroids (Classes I - III in the US, Classes III - IV in Europe), vitamin D analogs, keratolytics, or coal tar (except on the scalp, palms, groin, and / or soles of the feet) within 2 weeks of BL visit; ultraviolet light / Dead Sea therapy within 4 weeks of BL visit, or the predicted need for these treatments during the above trial period; renal or hepatic insufficiency, poorly controlled concomitant diseases, and pregnancy / lactation.

[0061] Evaluation of Efficacy and Safety The primary evaluation items included the proportion of patients achieving PASI75 (superiority) and safety in the picrilidone 2 mg and 3 mg BID groups compared with placebo at week 16. The secondary evaluation items at week 16 compared the picrilidone groups with placebo and included the proportion of patients achieving PASI50, the proportion of patients achieving 0 or 1 in the PGA2 score (a PASI-based scale calculated using the intensity grading of elements of the PASI score; specifically, the mean of the PASI erythema, infiltration, and desquamation scores [Gordon, K.B. et al., N Engl J Med 373, 136-144 (2015)]), and the proportion of patients experiencing improvement from BL in the psoriasis-specific quality-of-life assessment index (PDI). Further secondary evaluation items were evaluated at week 32, comparing the picrilidone groups with apremilast. These items included the proportion of patients achieving PASI75, PASI50, 0 or 1 in PGA2, and the proportion of patients experiencing improvement from BL in the PDI. PK analysis, including calculating the peak drug concentration (C max ) in the blood stream after dosing, was performed at weeks 0, 8, and 16.

[0062] Safety evaluations included adverse events (TEAEs) occurring during treatment and changes in vital signs, physical examinations, clinical laboratory tests (liver, kidney, hematology, chemistry, and urine tests), and electrocardiogram findings.

[0063] Statistical Analysis Overall, four types of analysis populations were defined as follows: The safety population included all patients who received at least one dose of picrilidone; The intention-to-treat (ITT) population included all members of the safety population who had at least one PASI score recorded after BL, excluding patients who discontinued prior to week 16 due to COVID-19-related trial holds; the modified ITT (mITT) population was used for the efficacy analysis at week 16 and included all ITT patients except for one patient in the placebo group who was excluded due to a major protocol violation not captured in the initial data; and finally, the per-protocol (PP) population was used for the analysis at week 32 and included all ITT patients who had no major protocol violations at week 16 or earlier and who had completed week 16 of the trial. Exclusions from the PP population were finalized prior to any non-blind analysis. Analyses conducted over 32 weeks were performed separately for patients randomized initially to pimecrolimus or apremilast and for patients randomized initially to the placebo group.

[0064] Descriptive statistics were used to summarize patient characteristics and safety. Treatment-emergent adverse events (TEAEs) were reported by treatment group for each of the 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 for the same PT, that patient was counted only once.

[0065] For the efficacy analysis, missing values were imputed. In the primary efficacy analysis, missing values due to discontinuation were considered as no response after discontinuation and were referred to as non-responder imputation (NRI); intermediate missing values were imputed using last observation carried forward (LOCF). Missing values for the secondary efficacy analysis were also imputed using NRI. p-values for the primary efficacy analysis and for the secondary analysis comparing pimecrolimus to placebo were determined by normal approximation for comparing two binomial proportions (NAB). The secondary analysis comparing pimecrolimus to apremilast was a non-inferiority analysis with a 10% non-inferiority margin using NAB. Data are presented as ratio / mean ± standard error.

[0066] All statistical tests were two-sided, and p < 0.05 was considered statistically significant.

[0067] Result A multi-site, randomized, placebo and active comparator double-blind trial of the third phase was conducted to evaluate the efficacy and safety of picrilidnson (IB-MECA, CF101) in patients with moderate to severe plaque psoriasis.

[0068] Patient A total of 701 patients with moderate to severe plaque psoriasis were screened. Patients meeting the eligibility criteria (N = 529) were randomized to picrilidnson 2 mg BID (N = 151), picrilidnson 3 mg BID (N = 142), apremilast (N = 142), or placebo (N = 94).

[0069] Overall, across all treatment groups, approximately one-third of all patients (n = 158, 29.9%) discontinued treatment in the first segment of the trial (0 - 16 weeks), particularly due to COVID-19 related trial holds (n = 93, 17.6% across all groups). Additional reasons for discontinuation included patient request (n = 39, 7.4%) and TEAE (n = 7, 1.3%).

[0070] The baseline patient and disease characteristics of the treatment-emergent safety population are shown in Table 1, indicating a well-balanced distribution across the study groups. The majority of the patients examined were male, and the median (range) age of the entire examined population was 49 (19 - 81) years; all but one were white. The median (range) disease duration for all patients was 12 (0 - 67) years and was similar across treatment groups.

[0071]

Table 1

[0072] Efficacy Compared with Placebo (Week 16) The primary evaluation items of the above-mentioned test were met. At week 16, patients who received 3 mg of picrilidenone showed statistically significant improvement compared to placebo in the mITT population as measured by the affected area and the Psoriasis Area and Severity Index (PASI) 75 response: picrilidenone 3 mg: 9.7% ± 1.8% vs. placebo: 2.6% ± 1.8% (p = 0.037) (Figure 2). A higher proportion of patients in the picrilidenone 2 mg BID group achieved PASI 75 compared to placebo at week 16 in the mITT population, but 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).

[0073] Regarding the secondary evaluation item of the proportion of patients who achieved PGA 2 at week 16 in the mITT population (Figure 3), the proportion was higher with picrilidenone 3 mg BID (10.7% ± 3.0%) and 2 mg BID (11.8% ± 2.8%) than with placebo (3.8% ± 2.2%). The difference observed between picrilidenone 3 mg BID and placebo was close to statistical significance (p = 0.068), and it was significant for 2 mg BID (p = 0.027).

[0074] Other secondary evaluation items evaluated at week 16 for the mITT population included the proportion of patients who achieved PASI 50 and the proportion of patients who improved from BL in PDI, and neither picrilidenone dose showed statistically significant superiority over placebo. The proportion of patients who achieved PASI 50 was 19.4% with picrilidenone 3 mg BID, compared to 15.4% with placebo (p = 0.475). It was 26.0% with picrilidenone 2 mg BID, and the difference compared to placebo showed a trend close to statistical significance (p = 0.060). The proportion of patients who achieved improvement in PDI from BL was 58.3%, 63.3%, and 60.3% with 3 mg BID, 2 mg BID, and placebo, respectively (p = 1.00 and p = 0.70 for each comparison to placebo).

[0075] Efficacy compared to apremilast in patients randomized to active treatment first (Week 32) A non-inferiority assessment of picrolidone vs apremilast was performed at Week 32 for the PP population, which included patients randomized to active treatment first. For the proportion of patients achieving PASI75, non-inferiority was not shown for 3 mg BID vs apremilast (17.0% and 26.2% respectively, p = 0.881), or for picrolidone 2 mg BID vs apremilast (20.8% and 26.2% respectively, p = 0.429). The proportion of patients achieving PASI50 was lower at both picrolidone doses compared to apremilast and non-inferiority was not shown (picrolidone 3 mg BID, 2 mg BID, and apremilast at 19.3%, 17.0%, and 25.2% respectively; p = 0.49 and p = 0.75 for each comparison to apremilast). Similarly, the proportion of patients with a PGA2 of 0 or 1 was also lower (at both doses) compared to apremilast and non-inferiority was not shown (picrolidone 3 mg BID, 2 mg BID, and apremilast at 15.9%, 18.9%, and 24.3% respectively; p = 0.777 and p = 0.417 for each comparison to apremilast).

[0076] A higher proportion of patients in the picrolidone 3 mg BID group achieved improvement from BL in the PDI compared to apremilast (58.0% vs 55.1%). The test for non-inferiority was in a significantly close trend (p = 0.072, Figure 4). The corresponding proportion at 2 mg BID was 48.1% and non-inferiority to apremilast was not shown (p = 0.66).

[0077] Safety Piclidenone 2 mg BID and 3 mg BID were well tolerated throughout the 32-week study period, and the frequency of TEAE did not increase with higher piclidenone doses (Table 2). The safety profiles of both piclidenone doses were generally comparable to those of placebo used only from Week 0 to Week 16. Furthermore, the safety profile of piclidenone was more favorable than that of apremilast, which was associated with higher frequencies of nervous system disorders (1.7% for each piclidenone dose vs. 9.6% for apremilast) and digestive diseases (2.8% for piclidenone 2 mg BID and 1.2% for piclidenone 3 mg BID vs. 7.3% for apremilast). The TEAEs occurring in >2% of patients in the piclidenone groups were only 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). Also, the cumulative risk with piclidenone was not observed in treatment beyond Week 16 if all patients received active treatment.

[0078] Overall, there were 3 severe adverse reactions that occurred during treatment in patients who received active treatment, including 1 case (arterial embolism) in a patient who received piclidenone 2 mg BID; 1 case (osteomyelitis) in a patient who received piclidenone 3 mg BID, and 1 case (pneumonia) in a patient who received apremilast; none of which were considered by the investigator to be drug-related. Nine patients discontinued the trial due to 10 TEAEs (7 cases from Week 0 to Week 16 and 2 cases from Week 16 to Week 32), including 1 case each in the placebo and apremilast groups, 2 cases in the piclidenone 2 mg BID group, and 5 cases in the piclidenone 3 mg BID group. None of these events were considered by the investigator to be drug-related. Electrocardiograms did not show clinically significant drug effects on QTcF or other parameters throughout the treatment course in all groups. No other safety events of note occurred throughout the study period, and no deaths were reported.

[0079]

Table 2

[0080] Pharmacokinetics (PK) PK data showed that exposure to picidenoson, measured by both Cmax and AUC (area under the curve), was similar between the 2 mg BID group and the 3 mg BID group (Figure 5).

Claims

1. A suitable daily dose of approximately 6 milligrams (mg) is 1-[N ６ A pharmaceutical composition for use in the treatment of psoriasis, comprising -(3-iodobenzyl)-adenine-9-yl]-β-D-ribofronamide (IB-MECA) as an active ingredient.

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

3. The pharmaceutical composition according to claim 1, in a dosage form suitable for administration once or twice a day, with a total daily dose of approximately 6 mg.

4. The pharmaceutical composition according to claim 1 in an oral solid dosage form.

5. The pharmaceutical composition according to claim 4, wherein the solid dosage form comprises 3 mg of IB-MECA administered twice daily.

6. The pharmaceutical composition according to claim 1, in a dosage form selected from pills, tablets, and capsules.

7. IB-MECA for use in the treatment of psoriasis, in an amount suitable for providing a total daily dose of approximately 6 mg of IB-MECA to patients requiring treatment.

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

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

10. The IB-MECA according to claim 9, formulated in a solid dosage form.

11. The IB-MECA according to claim 10, wherein the solid dosage form is selected from the group consisting of pills, tablets, and capsules.

12. IB-MECA according to claim 7, in a dosage form suitable for administering 3 mg of IB-MECA twice daily.

13. A package comprising a pharmaceutical composition as defined in claim 1 and instructions for administering the pharmaceutical composition to a subject requiring treatment of psoriasis at a daily dose of about 6 mg of IB-MECA.

14. The package according to claim 13, wherein the pharmaceutical composition comprises 3 mg of IB-MECA and the instructions include administering the pharmaceutical composition to a subject twice a day.

15. The pharmaceutical composition according to claim 1, or IB-MECA according to claim 7, or the package according to claim 13, wherein the psoriasis is moderate to severe psoriasis vulgaris.

16. For patients who require it, a daily dose of approximately 6 milligrams (mg) is given as 1-[N ６ A method for treating psoriasis, comprising administering -(3-iodobenzyl)-adenine-9-yl]-β-D-ribofronamide (IB-MECA) or a pharmaceutical composition containing IB-MECA.

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

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

19. The method according to claim 16, wherein the IB-MECA or pharmaceutical composition is administered as a solid dosage form containing 3 mg of IB-MECA, administered twice daily.

20. The method according to claim 19, wherein the solid dosage form is selected from pills, tablets, and capsules.

21. The method according to claim 16, wherein the psoriasis is moderate to severe psoriasis vulgaris.

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