DELAYED-RELEASE GLUCOCORTICOID TREATMENT OF RHEUMATOID DISEASE

Abstract

The present invention refers to the treatment of a rheumatic disease and/or osteoarthritis by administering a delayed-release dosage form of a glucocorticoid to a subject in need thereof.

Claims

1.-79. (canceled)

80. A method for the treatment of a patient suffering from signs and symptoms of an underlying rheumatic disease and/or osteoarthritis, which comprises administering to said patient an effective amount of prednisone contained in a delayed-release dosage form, wherein said treatment is administered once daily for at least about two weeks, wherein said treatment with said prednisone contained in a delayed-release dosage form provides an increased reduction in the duration of morning stiffness as compared to treatment with prednisone in an immediate release dosage form, and wherein the delayed release dosage form is a tablet or a capsule.

81. The method of claim 80, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about four weeks.

82. The method of claim 80, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about eight weeks.

83. The method of claim 80, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about twelve weeks.

84. The method of claim 80, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about twelve months.

85. The method of claim 80, wherein the delayed-release dosage form has a lag time of from about 2 hours to about 6 hours after administration.

86. The method of claim 80, wherein the delayed-release dosage form has a lag time of from about 3 hours to about 5 hours after administration.

87. The method of claim 80, wherein the delayed-release dosage form has a dissolution time of equal to or less than about 2 hours after the lag time is reached.

88. The method of claim 80, wherein the delayed-release dosage form has a drug release behavior which is independent of pH.

89. A method for the treatment of a patient suffering from signs and symptoms of an underlying rheumatic disease and/or osteoarthritis, which comprises administering to said patient an effective amount of prednisone contained in a delayed-release dosage form, wherein said treatment is administered once daily for at least about two weeks, wherein said patient has previously undergone treatment with a disease-modifying antirheumatic drugs (DMARD), and wherein the delayed release dosage form is a tablet or a capsule.

90. The method of claim 89, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about four weeks.

91. The method of claim 90, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about eight weeks.

92. The method of claim 91, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form one for at least about twelve weeks.

93. The method of claim 92, wherein the treatment comprises administration of the prednisone contained in a delayed-release dosage form for at least about twelve months.

94. The method of claim 89, wherein the rheumatic disease is rheumatoid arthritis, ankylosating spondylitis and/or polymyalgia rheumatica.

95. The method of claim 89, wherein the delayed-release dosage form has a lag time of from about 2 hours to about 6 hours after administration.

96. The method of claim 89, wherein the delayed-release dosage form has a lag time of from about 3 hours to about 5 hours after administration.

97. The method of claim 89, wherein the delayed-release dosage form has a dissolution time of equal to or less than about 2 hours after the lag time is reached.

98. The method of claim 89, wherein the delayed-release dosage form has a drug release behaviour which is independent of pH.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1 shows duration of Morning Stiffness: Relative Change from Baseline in % (SEM) per week of treatment in the ITT population.

[0043] FIG. 2 shows duration of Morning Stiffness: Relative Change from Baseline in % (SEM) per month of treatment in the ITT population.

[0044] FIG. 3 shows IL 6 values (median) under treatment of Prednisone delayed release tablets.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention refers to the use of a delayed-release dosage form of a glucocorticoid. The release of the active ingredient is preferably delayed for a time period of 2-10 hours after intake, preferably 2-6, more preferably 3-5 hours after intake the active ingredient may be released in the upper sections of the intestine and/or in the lower sections of the intestine. More preferably, the active ingredient is released in the upper sections of the intestine within a period of 2-6 hours. The delayed-release dosage form is preferably administered to the patient at or before bedtime, more preferably in the evening, e.g. from about 9:00 pm to about 11:00 pm. Because inflammation is accompanied with circadian fluctuations in the concentration of pro-inflammatory cytokines (such as Interleukin-6) which peaks during sleeping hours, bedtime administration allows an efficacious concentration of the active ingredient to be present when such concentration peaks.

[0046] The delayed-release dosage form is preferably a tablet, e.g. as described in WO 2006/027266, which is herein incorporated by reference. The dosage form preferably comprises [0047] (a) a core having at least one glucocorticoid-active ingredient and having at least one swellable adjuvant and/or a disintegrant such that the active ingredient is rapidly released from the dosage form when the core is contacted with gastrointestinal fluids, and [0048] (b) an inert, e.g. a non-soluble and non-swellable coating pressed onto the core, said coating being capable of preventing substantial release of the active ingredient for a defined time period following ingestion of the dosage form.

[0049] The inert coating initially prevents release of the active ingredient or the active ingredient combination over an exactly defined period, so that no absorption can occur. The water present in the gastrointestinal tract penetrates slowly in through the coating and, after a time which is previously fixed by the pressure for compression, reaches the core. The coating ingredients show neither swelling nor diluting of parts of the coating. When the core is reached, the water penetrating in is very rapidly absorbed by the hydrophilic ingredients of the core, so that the volume of the core increases greatly and, as a consequence thereof, the coating completely bursts open, and the active ingredient and the active ingredient combination respectively is released very rapidly.

[0050] A particularly advantageous embodiment of this press-coated delayed-release tablet is achieved when a previously compressed core tablet is subsequently compressed with a multilayer tablet press to a press-coated tablet.

[0051] The tablet coating typically consists of the following materials in order to achieve a delayed release profile: [0052] polymer or copolymer of acrylic acid, methacrylic acid etc. (e.g. Eudragits or Carbopol), [0053] cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose, cellulose acetate, [0054] polyvinyl alcohol, [0055] polyethylene glycol, salts of higher fatty acids, esters of monohydric or polyhydric alcohols with short-, medium- or long-chain, saturated or unsaturated fatty acids. Specifically, stearic acid triglycerides (e.g. Dynersan) or glycerol behenate (e.g. Compritol) are used.

[0056] In addition, further adjuvants should also be added to these materials so that the tablet coating can be compressed. Typically used here are fillers such as lactose, various starches, celluloses and calcium hydrogen phosphate or di-basic calcium phosphate. The glidant used is normally magnesium stearate, and in exceptional cases also talc and glycerol behenate. A plasticizer is often also added to the coating material, preferably from the group of polyethylene glycol, dibutyl phthalate, diethyl citrate or triacetin.

[0057] In order to achieve an optimal release profile, the tablet core must also fulfil certain tasks and exhibit certain properties. Thus, after the lag phase has elapsed, a rapid release profile is achieved if typical disintegrants are added to the inner core, which are derived for example from the group of the following substances: cellulose derivatives, starch derivatives, crosslinked polyvinylpyrrolidone. The use of a blowing agent, for example resulting from a combination of a weak acid and a carbonate or bicarbonate, may also promote rapid release. The tablet core typically consists additionally of matrix or filling ingredients (e.g. lactose, cellulose derivatives, calcium hydrogen phosphate or other substances known from the literature) and lubricant or glidant (usually magnesium stearate, in exceptional cases also talc and glycerol behenate).

[0058] The size of the core tablet preferably should not exceed 6 mm (preferably 5 mm) in diameter, because otherwise the press-coated tablet becomes too large for convenient ingestion. As a result thereof, the dosages of the active ingredients are in the range from 0.1 to 50 mg, very particularly between 1 and 20 mg.

[0059] The in vitro release profile of the dosage form according to the invention is preferably such that less than 5% of the active ingredient is released during the lag phase. After the release phase has started, preferably ≧80%, particularly preferably ≧90%, of the active ingredient is released within one hour. More preferably, the delayed-release dosage form has a dissolution time of equal to or less than about 2 hours after the lag time has been reached). The in vitro release is preferably determined using the USP paddle dissolution model in water.

[0060] The employed active ingredients are derived from the group of glucocorticoids and all show comparable physicochemical properties. Such include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort, triamcinolone, or the corresponding pharmaceutically acceptable salts and/or esters thereof. This applies in particular to prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fluocortolone, cloprednole, and deflazacort or the corresponding pharmaceutically acceptable salts and/or esters thereof.

[0061] In the present case of the delayed-release tablet, the following combination of core materials and coating materials has proved to be particularly suitable for achieving a time- and site-controlled release with exclusion of pH and food influences:

[0062] The coating preferably comprises: [0063] hydrophobic, waxy substances with an HLB value of less than about 5, preferably around 2. Carnauba wax, paraffins, cetyl ester waxes are preferably employed therefor. Glycerol behenate has proved to be particularly suitable. The use of about 20-60%, in particular about 30-50%, in the coating has proved to be very advantageous; [0064] non-fatty, hydrophobic filling materials such as calcium phosphate salts, e.g. dibasic calcium phosphate. The use of about 25-75% of these filling materials, in particular of about 40-60%, in the coating has proved to be very advantageous here; [0065] in addition, the tablet coating preferably also consists of binders, e.g. polyvinylpyrrolidone (PVP), typically in concentrations of about 4-12%, specifically about 7-10%, and glidants such as magnesium stearate, in concentrations of about 0.1-2%, in the specific case of about 0.5-1.5%. Colloidal silicon dioxide can for example be used as flow regulator, normally in concentrations of about 0.25-1%. In addition, to distinguish different dosages, a colorant can be added to the tablet coating, preferably an iron oxide pigment in concentrations of about 0.001-1%.

[0066] The core tablet preferably comprises: [0067] an active ingredient or an active ingredient combination from the group of glucocorticoids, preferably prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort, and triamcinolone, and the corresponding salts and esters thereof. The dosages of the active ingredients are in the region of about 0.1-50 mg, very especially between about 1 and 20 mg; [0068] in addition, the core tablet preferably comprises a filler such as, for example, lactose, starch derivatives or cellulose derivatives. Lactose is preferably employed. The filler is typically present in concentrations of about 50-90%, specifically of about 60-80%. A disintegrant is additionally present and is typically crosslinked PVP or sodium carboxymethylcellulose, typically in concentrations of about 10-20%. It is additionally possible for a binder, e.g. PVP, to be present, typically in concentrations of about 2-10%, specifically of about 5.5-9%, and a lubricant such as magnesium stearate, in concentrations of about 0.1-2%, in the specific case of about 0.5-1.5%. Colloidal silicon dioxide is normally used as flow regulator, normally in concentrations of about 0.25-1%. It is additionally possible, for visually distinguishing the core from the coating, to add a colorant, preferably an iron oxide pigment in concentrations of about 0.01-1%.

[0069] Preferably, the delayed-release dosage form is administered as a long-term treatment to a subject in need thereof for a time sufficient to reduce and/or abolish the disease and/or disease symptoms. The long term treatment usually comprises daily administration of the medicament for an extended period of time, e.g. for at least two weeks, preferably for at least 4 weeks, more preferably for at least 8 weeks, even more preferably for at least 12 weeks, and most preferably for at least 6 months or at least 12 months.

[0070] According to the present invention refers to the novel treatment of groups of patients suffering from rheumatic diseases and/or osteoarthritis. These patient groups are selected from: [0071] (i) patients with severe diseases characterized by a Disease Activity Score (DAS) of >5.1 (Le Loet 2006) and/or a Physicians Assessment; [0072] (ii) patients with moderate diseases characterized by a Disease Activity Score (DAS) of >3.2 but <5.1 and/or a Physicians Assessment; [0073] (iii) patients with mild diseases characterized by a Disease Activity Score (DAS) of <3.2 and/or a Physicians Assessment; [0074] (iv) patients with short disease duration of less than 2 years, [0075] (v) patients with mid-term disease duration of 2-5 years, and [0076] (vi) patients with long-lasting disease duration of more than 5 years.

[0077] Further patient groups may be selected from: [0078] (i) patients with severe, long lasting morning stiffness characterized by a duration of morning stiffness >180 min, [0079] (ii) patients with moderate morning stiffness between 100 and 180 min, [0080] (iii) patients with mild morning stiffness of less than 100 min, [0081] (iv) patients with severe, long lasting pain characterized by a VAS scale with >70 mm, [0082] (v) patients with moderate pain characterized by a VAS scale with >50-70 mm, [0083] (vi) patients with mild pain characterized by a VAS scale with <50 mm.

[0084] Further patient groups may be selected from:

(i) patients with high Interleukin 6 levels, e.g. more than 3000 IU/I;
(ii) patients with medium Interleukin 6 levels, e.g. between 3000 and 1000 IU/I;
(iii) patients with low Interleukin 6 levels, e.g. less than 1000 IU/1.

[0085] Further patient groups may be selected from: [0086] (i) patients who have been pre-treated with an immediate release dosage form of a glucocorticoid; [0087] (ii) patients who are refractory to treatment with an immediate-release dosage form of a glucocorticoid, and [0088] (iii) glucocorticoid naive patients.

[0089] Further patient groups may be selected from: [0090] (i) patients who have been pre-treated with other medicaments like a NSAID, a DMARD, a TNFα inhibitor and/or an analgetic agent or any combination thereof, and [0091] (ii) patients who have not been pre-treated with any other medicaments like a NSAID, a DMARD, a TNFα inhibitor, an Interleukin 6 inhibitor and/or an analgetic agent.

[0092] By means of administering a delayed-release tablet, the daily dose of the glucocorticoid may be substantially reduced compared to an immediate-release tablet of the glucocorticoid. Thus, the disease-inhibiting effect may be obtained by a significantly lower dose of the active ingredient, whereby the occurrence and/or intensity of site effect is diminished. For example, the daily dose of the glucocorticoid can be reduced by at least 10%, more preferably by at least 20%, e.g. by 10-50% compared to an immediate-release tablet. Thus, the reduced daily dose of prednis(ol)one in Prednisone delayed-release is preferably in the range of 1 to 5 mg/day compared to 6-10 mg/day for a standard IR tablet.

[0093] The treatment according to the present invention may comprise the treatment of a rheumatic disease and/or osteoarthritis without any further medicament. On the other hand, the invention may comprise the treatment of a rheumatic disease and/or osteoarthritis in combination with at least one further medicament which is preferably selected from the groups of NSAIDs, DMARDs, TNF a inhibitors, IL-6 inhibitors, analgetic agents or combinations thereof. Especially preferred is a combination with Tarenflurbil.

[0094] NSAIDs are preferably selected from arylalkanoic acids (Diclofenac, Indometacin, Sulindac) from 2-arylpropionic acids (Carprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, Laxoprofen, Naproxen, Tiaprofenic acid), from N-arylanthranilic acids (Mefenamic acid, Meclofenamic acid), from Oxicams (Piroxicam, Meloxicam) or from Coxibs (Celecoxib, Parecoxib, Etoricoxib) or from combinations thereof. Especially preferred is a combination with Tarenflurbil.

[0095] DMARDs are preferably selected from gold preparations, chloroquine, azathioprine, sulfasalazine, cyclophosphamide, penicillamine, hydroxychloroquine, methotrexate, thorium dioxide suspension, levamisole, cyclosporin, interferone, leflunomide or from combinations thereof.

[0096] TNF a inhibitors and IL 1 inhibitors are preferably selected from antibodies or soluble receptors such as etanercept, inflixima, anakinra, adalimumab and from cominations thereof.

[0097] IL-6 inhibitors are preferably selected from antibodies or soluble receptors such as tocilizumab.

[0098] Analgetic agents are preferably selected from salicylates (Aspirin, Methyl salicylate, Diflunisal, Benorylate, Faislamine, Amoxiprin), from pyrazolidine derivatives (Phenylbutazone, Oxyphenylbutazone) or paracetamol or from combinations thereof.

[0099] The dose of the at least one further medicament may be substantially reduced e.g. by at least 10%, preferably by at least 20%, e.g. by 10-50%. Alternatively, the first usage of TNF a inhibitors or IL-6 inhibitors can be postponed to a later point in time.

[0100] The present invention particularly refers to the treatment of a rheumatic disease selected from rheumatoid arthritis, ankylosating spondylitis, polymyalgia rheumatica and/or to the treatment of osteoarthritis. Based on the results of the clinical trials described in the present application, it is evident that the delayed-release dosage form of a glucocorticoid, particularly a long-term treatment, is of therapeutic benefit. Particularly in the case of osteoarthritis or a rheumatic disease having an osteoarthritic component, the administration of the delayed-release dosage form is effective without having undesired side effects.

[0101] The dose of the glucocorticoid may vary during the course of treatment. For example, the patient may be administered a relatively high dose during the initiation of therapy (e.g., about 10-40 mg/day or higher of prednisone, or an equivalent amount of another glucocorticoid), which may be reduced downward over a period of time (e.g., over 3-4 weeks) according to the patient's response, to a maintenance therapy dose of about 10 mg/day or less of prednisone, or an equivalent amount of another glucocorticoid. Alternatively, the patient may be started on a relatively low dose, which may be adjusted upward over a period of time (e.g., over 3-4 weeks) to a maintenance therapy dose of about 10 mg/day or less of prednisone, or an equivalent amount of another glucocorticoid.

[0102] Further, the present invention is described in more detail by the following examples.

Example

[0103] Clinical Studies.

[0104] The clinical development program supporting the present application for the delayed-release prednisone tablet “Prednisone delayed-release” comprised 3 phase I studies and 1 phase III study: [0105] Phase I studies: These 3 randomized, open-label, crossover studies on 69 healthy men investigated the comparative bioavailability and pharmacokinetic characteristics of 6 experimental galenic delayed-release formulations each containing 5 mg prednisone. The studies were performed to allow selection of a delayed-release tablet with appropriate characteristics for evening administration to RA patients (i.e. a suitable lag time and high bioavailability that was not affected by food). Single doses of each of the delayed-release tablets were compared to a single dose of a reference immediate release (IR) prednisone tablet (Decortin® 5 mg tablets marketed by Merck KGaA). [0106] Phase III study: In this randomized, parallel-group, double-blind, double-dummy study on 288 adult RA patients, the final prednisone delayed-release tablet formulation was administered in the evening for 12 weeks. The daily prednisone dose of 3 to 10 mg was achieved with 1 and 5 mg tablets. Efficacy and safety were compared with the reference IR product given in the morning.

[0107] This is a novel study design which was not used by Arvidson (1997) or Karatay (2002) as patients in these studies were corticoid naive. In those studies the administration of a standard IR prednis(ol)one tablet at 2.00 and 8.00 was compared.

Study Design and Methodology

[0108] Study Design.

[0109] The studies were specifically designed to compare the efficacy and safety of Prednisone delayed-release given in the evening with standard IR prednisone (Decortin®, Merck KGaA) given in the morning at 08:00 over a period of 12 weeks. Prednisone delayed-release and the reference product both contained the same drug (prednisone) and differed solely with respect to the timepoint at which this was released in the gastrointestinal tract. Timing of the evening dose (22:00.+−0.30 min) was based on results from a previous pharmacokinetic study with Prednisone delayed-release which showed first detectable plasma concentrations of prednisone and its active metabolite prednisolone after 4 hours and maximal plasma concentrations about 6 h after administration. This specific plasma profile with Cmax at 04:00 is expected to suppress the known early morning increase of pro-inflammatory cytokines, and thus reduce morning stiffness.

[0110] Inclusion of a placebo arm was not considered necessary or ethical due to the proven efficacy of prednisone. Blinding was essential in this study to avoid bias. As the Prednisone delayed-release tablets and reference product tablets differed in appearance a double-dummy technique was used to maintain the treatment blind.

[0111] The study had a 1- to 2-week screening period that was followed by a 12-week double-blind treatment period with visits after 2 and 6 weeks. This 12-week period was considered to be sufficiently long to demonstrate any differences in the primary and secondary efficacy endpoints (see below). At the end of the 12-week double blind period, patients who completed the 12-week double-blind period were offered to continue in an open-label 9-month follow up period, during which all patients received active treatment with Prednisone delayed-release.

[0112] Prednisone Dose.

[0113] Patients were to continue on the same stable low dose of prednisone (or equivalent) that they received in the month before entering the study. During the study prednisone doses of 3 to 10 mg/day were achieved with appropriate combinations of Prednisone delayed-release or IR tablets containing 1 and 5 mg prednisone; daily doses of 2.5 and 7.5 mg prednisone were rounded to 3 and 8 mg, respectively. A constant low prednisone dose was given throughout the treatment phase to ensure that any differences between the treatment groups were not due to dose changes.

[0114] Primary Objective and Efficacy Endpoint.

[0115] The primary objective of the study was to show whether administration of the new delayed-release formulation of prednisone (i.e. Prednisone delayed-release) in the evening was superior to the standard morning administration of immediate-release (IR) prednisone in reducing the duration of morning stiffness. The patient diary card was appropriately designed to capture relevant clock times in minutes: wake-up, morning medication intake, resolution of morning stiffness. The primary variable was “the relative change in duration of morning stiffness from baseline at individual study end in the double-blind treatment phase”, whereby the duration of morning stiffness was the difference between the time of resolution of morning stiffness and the time of awakening. Morning stiffness was chosen as the primary variable because it was expected to be directly affected by inhibition of night-time IL-6 peaks after delayed release of prednisone.

[0116] Secondary Efficacy Endpoints.

[0117] In addition to morning stiffness, the study included a comprehensive battery of supportive secondary endpoints that were based on regulatory recommendations (CPMP/EWP/556/95 rev 1). Patients assessed their quality of sleep, pain intensity (VAS), and global disease activity (VAS). They also documented their use of analgesics and completed validated questionnaires on their health status (HAQ) and quality of life (SF36). Investigators counted the numbers of swollen and tender joints (28 joints) and assessed global disease activity (5-point scale). Laboratory variables (ESR, CRP, IL-6) were assessed from blood samples taken as early as possible in the morning to investigate the inflammatory state of the disease. Osteocalcin was also measured as an indicator of bone metabolism.

[0118] Two validated composite variables were used: the disease activity score (DAS 28) and the ACR20 responder rate. The DAS 28 was computed from the joint scores, the ESR and the patient's global assessment of disease activity. An ACR responder was defined as a patient with improvement of at least 20% of the baseline values in the tender joint count, swollen joint count and at least 3 of the following 5 variables: pain intensity, investigator global assessment, patient global assessment, HAQ disability index, or ESR.

[0119] Inclusion criteria were designed to enroll adult patients (18 to 80 years) with active RA who were typical of the general RA population being treated with a combination of stable corticoid medication and DMARDs. Patients had to have a documented history of RA and present with active symptoms of disease, i.e. morning stiffness of 45 min, pain ≧30 mm (VAS), ≧3 painful joints, ≧1 swollen joints and elevated ESR and/or CRP.

[0120] Patients had to have been treated with the following state-of-the-art RA medications for at least 3 months before entering the study: [0121] DMARDs (unless they were not tolerated) [0122] Prednis(ol)one, with a low, stable dose of 2.5 to 10 mg prednisone (or equivalent) for at least 1 month prior to screening.

[0123] Patients were to continue on their RA medications at the same dose throughout the 12-week double-blind treatment phase. These restrictions are considered appropriate because they ensure that any differences between the treatment groups were due to the different dosing modalities of prednisone not to dose changes in the corticoid or concomitant DMARDs.

Study Results

[0124] 288 randomized patients were treated in total, 144 patients with Prednisone delayed-release and 144 with the IR reference product. The baseline characteristics of the two treatment groups were comparable (mean values for the overall population): age (55 years), gender (85% female), morning stiffness (173 min), disease duration (115 months), DAS 28 (5.9), daily dose of prednis(ol)one (6.6 mg), medications prior to screening (DMARDs 94%, non-steroidal anti-inflammatory drugs [NSAIDs] 80% patients). Also the medical history of the patients in both treatments are comparable. Table 1 summarizes the Disease characteristics. Patients with different disease duration (short, mid-term and long-lasting) and different disease activity (DAS: mild, moderate and severe) were included.

TABLE-US-00001 TABLE 1 Disease characteristics at baseline (ITT population) Prednisone Standard Disease delayed IR characteristics -release Prednisone Total at baseline (N = 144) (N = 144) (N = 288) RA No. of Subjects n (%) 144 144 288 (100.0) (100.0) (100.0) MeanDuration months 115.1 115.4 115.3 Duration <2 years, 19 18 37 n (%) (13.2) (12.5) (12.8) 2-5 years, 37 37 74 n (%) (25.7) (25.7) (25.7) 5-10 33 31 64 years, n (%) (22.9) (21.5) (22.2) >10 years, 55 58 113 n (%) (38.2) (40.3) (39.2) Pre-treatment (yes) 144 144 288 (100.0) (100.0) (100.0) Stable dose [mg] Mean 6.5 6.7 6.6 of prednis(ol)one DAS28 Mean 5.8 5.9 5.9 SD 0.8 0.9 0.8 Range 3.3-8.1 3.7-7.7 3.3-8.1 Disease Asymptomatic 0 (0.0) 0 (0.0) 0 (0.0) activity Mild 13 (9.0) 14 (9.7) 27 (9.4) (physician's Moderate 103 (71.5) 102 (70.8) 205 (71.2) Assessment) Severe 28 (19.4) 28 (19.4) 56 (19.4) [n(%)] Very Severe 0 (0.0) 0 (0.0) 0 (0.0) Pain Intensity mean 57.9 59.7 58.8 (HAS-VAQ) SD 14.8 15.8 15.3 [mm] Range 18-95 25-96 18-96 HAS-DI score mean 1.5 1.5 1.5 SD 0.6 0.5 0.5 Range 0.0-2.9 0.0-2.8 0.0-2.9

Efficacy Results

[0125] Primary efficacy variable and morning stiffness. As planned, the primary efficacy analysis in the study was performed on the intention-to-treat population (i.e. all randomized patients as randomized) using “last observation carried forward” methodology.

TABLE-US-00002 TABLE 2 Duration of morning stiffness after 12 weeks of treatment (intention-to-treat population) Duration of morning stiffness Prednisone delayed- Prednisone Standard (mean (SD)) release (N = 144) (N = 144) Baseline [min] 164.1 (101.4) 182.5 (125.0) (N =125) (N = 129) At Week 12 (Final week) 120.9 (140.5) 157.4 (145.6) [min] (N =127) (N = 131) Relative change [%] −22.66 (89.1) −0.39 (89.0) (N =125) (N = 129) Treatment difference LS mean (SD) [%] 22.4 (11.1) Lower limit of 95% CI 0.493 p-value 0.0226 (one-sided)

[0126] The primary variable was “the relative change in duration of morning stiffness from baseline at individual study end in the double-blind treatment phase”, whereby the duration of morning stiffness was the difference between the time of resolution of morning stiffness and the time of awakening. The reduction in duration of morning stiffness under Prednisone delayed-release treatment was higher than under standard IR prednisone throughout the 12-week treatment period.

[0127] At the end of the first week of treatment there was a difference of 10% between the two treatment groups. The relative reduction between baseline and final week of treatment was 22.7% in the Prednisone delayed-release group and 0.4% in the standard prednisone group. Thus, Prednisone delayed-release was shown to be superior to standard prednisone IR tablet in a statistically significant manner (p<0.025, one sided) and the primary study objective was met.

[0128] A difference between the two groups is obvious from the first week on, however the longer the treatment the more pronounced are the differences in favour for Prednisone delayed-release. This is illustrated in Table 3 and FIG. 1:

TABLE-US-00003 TABLE 3 Mean daily duration of morning stiffness per week (intention-to-treat population) Mean daily duration Prednisone Prednisone of morning stiffness delayed-release Standard per week (mean (SD)) (N = 144) (N = 144) Baseline [min] 164.1 (101.4) 182.5 (125.0) (N = 125) (N = 129) At Week 1 [min] 159.4 (127.3) 186.4 (135.6) (N = 126) (N = 131) Relative change [%] −1.4 (62.4) 9.3 (60.2) (N = 124) (N = 129) At Week 2 [min] 144.9 (136.4) 187.7 (154.4) (N = 123) (N = 131) Relative change [%] −12.5 (70.0) 8.1 (71.6) (N = 121) (N = 129) At Week 3 [min] 138.3 (137.1) 164.2 (137.2) (N = 122) (N = 127) Relative change [%] −13.8 (73.9) 0.3 (63.6) (N = 120) (N = 125) At Week 4 [min] 129.5 (128.3) 163.7 (124.2) (N = 117) (N = 123) Relative change [%] −23.3 (54.7) 3.5 (72.5) (N = 115) (N = 121) At Week 5 [min] 126.0 (126.9) 159.7 (128.5) (N = 117) (N = 121) Relative change [%] −25.9 (55.1) 6.0 (85.1) (N = 115) (N = 119) At Week 6 [min] 117.9 (128.2) 154.2 (123.7) (N = 112) (N = 119) Relative change [%] −28.3 (59.8) 5.3 (82.5) (N = 110) (N = 117) At Week 7 [min] 109.0 (113.9) 156.5 (144.9) (N = 109) (N = 119) Relative change [%] −33.5 (49.1) −2.6 (74.2) (N = 107) (N = 117) At Week 8 [min] 98.7 (93.8) 152.1 (125.3) (N = 105) (N = 116) Relative change [%] −37.1 (45.8) −5.2 (62.5) (N = 103) (N = 114) At Week 9 [min] 90.7 (87.5) 146.4 (123.1) (N = 107) (N = 116) Relative change [%] −41.3 (46.5) −5.6 (68.8) (N = 105) (N = 115) At Week 10 [min] 92.7 (90.8) 147.9 (134.1) (N = 105) (N = 117) Relative change [%] −40.5 (46.9) −5.0 (83.0) (N = 103) (N = 116) At Week 11 [min] 95.9 (97.2) 148.9 (136.4) (N = 103) (N = 116) Relative change [%] −37.7 (50.1) −1.2 (95.8) (N = 101) (N = 115) At Week 12 [min] 98.1 (100.5) 149.5 (134.8) (N = 102) (N = 111) Relative change [%] −33.1 (75.4) −3.4 (92.1) (N = 100) (N = 111)

[0129] The weekly assessment of the mean daily duration of morning stiffness revealed that the decrease and thus the improvement begins already after 2 weeks of treatment in the Prednisone delayed-release group. The mean daily duration of morning stiffness continues to decrease steadily thereafter, whereas in the prednisone standard group, there was no clear tendency for the changes during the 12-week treatment.

[0130] This result is surprising as Karatay showed in 2002 that such an effect[[s]] could not be expected.

[0131] Due to the superiority of Prednisone delayed-release against standard Prednisone of a reduction in the daily dose of e.g. 25-30% could be possible under

[0132] In the Phase III trial the superiority of a very low dose of Prednisone in the new delayed-release tablet compared to standard IR prednisone could be shown supporting the proposed dose reduction.

[0133] Table 4 shows the frequencies of starting stable doses of prednisone in the Prednisone delayed-release and standard prednisone groups of the intention-to-treat (ITT) population. The frequency profiles in both treatment groups were similar, with the most common dose being 5 mg (50% subjects), followed by 7 and 10 mg (approximately 20% each).

TABLE-US-00004 TABLE 4 Frequencies of stable doses of prednisone at start of study (ITT population) Number (%) subjects Stable Prednisone Standard Predsisone Dose delayed-release prednisone (mg) (N = 144) (N = 144) 2 1 (0.7) 0 (—) 3 8 (5.6) 2 (1.4) 4 1 (0.7) 1 (0.7) 5 72 (50.0) 73 (50.7) 6 1 (0.7) 0 (—) 7 28 (19.4) 30 (20.8) 8 4 (2.8) 3 (2.1) 9 0 (—) 0 (—) 10 29 (20.1) 35 (24.3)

[0134] The median value of the mean daily prednisone dose across all subjects in the ITT population was 5.18 mg. Subgroup analyses were performed on the primary efficacy variable (i.e. the relative change from baseline in duration of morning stiffness) in subjects with a mean daily prednisone dose 5.18 mg and >5.18 mg.

[0135] In order to investigate the comparability of subgroups, selected demographic and baseline characteristics were analyzed: age, gender, ethnic origin, body weight, body height, duration of RA, HAQ-DI, pain intensity (VAS), SF36, and DAS28. Comments on age, duration of RA, and DAS28 as the most clinically relevant parameters are included below. There were no clinically relevant imbalances between subgroups in the other baseline variables.

[0136] Descriptive statistics for baseline demographics and the primary efficacy variable are presented for mean daily prednisone doses of >5.18 mg and 5.18 mg in each of the treatment groups of the ITT population in Table 5. The difference for the primary efficacy variable between the treatment groups is also given (as calculated by ANOVA, model A).

TABLE-US-00005 TABLE 5 Baseline demographic variables and primary efficacy variable in subjects with a mean daily prednisone dose <5.18 mg or >5.18 mg* (ITT population) Prednisone delayed-release Standard prednisone (N = (N = 144) 144) Variable/subgroup N Mean (SD) N Mean (SD) Baseline demographic variables Age, years Mean daily dose ≦5.18 mg* 78 55.1 (10.5) 65 54.6 (11.9) Mean daily dose >5.18 mg* 65 54.3 (12.0) 77 56.1 (10.9) Duration of RA, months Mean daily dose ≦5.18 mg* 77 115.5 (98.4) 65 113.0 (111.4) Mean daily dose >5.18 mg* 65 116.3 (86.8) 77 117.1 (75.1) DAS28 score Mean daily dose ≦5.18 mg* 78 5.8 (0.8) 64 5.8 (0.9) Mean daily dose >5.18 mg* 65 5.8 (0.7) 76 6.0 (0.8) Duration of morning stiffness Mean daily dose ≦5.18 mg* Baseline, min 67 163.54 (109.92) 59 174.79 (132.47) Final week, min 69 119.25 (132.40) 60 169.36 (174.47) Relative change from baseline to 67 −26.93 (67.72) 59 7.88 (106.38) final week, % Difference between groups LS mean (SE), % 34.98 (15.57) 95% CI 4.13, 65.83 p-value 0.0134 (one-sided) Mean daily dose Baseline, min 57 164.81 (92.36) 68 189.74 (120.43) Final week, min 57 122.81 (152.12) 69 144.22 (113.49) Relative change from baseline to 57 −17.64 (110.12) 68 −8.76 (70.83) final week, % Difference between groups LS mean (SE), % 15.45 (16.14) 95% CI −16.54, 47.45 p-value 0.1702 (one-sided) *5.18 mg is the median value of the mean daily prednisone dose across all subjects in the ITT population. LS = least square, SE = standard error

[0137] There were no differences in mean age, mean duration of RA, or mean DAS28 score between subjects receiving a mean daily prednisone dose of ≦5.18 mg and those receiving a mean daily dose of >5.18 mg in either of the 2 treatment groups.

[0138] In the Prednisone delayed-release group, morning stiffness decreased in both dose subgroups, with a larger decrease in subjects with a mean daily prednisone dose ≧5.18 mg than in subjects with a daily dose >5.18 mg.

[0139] In the standard prednisone group, subjects with a mean daily dose ≦5.18 mg showed an increase in the duration of morning stiffness. In subjects with a mean daily dose >5.18 mg, morning stiffness decreased but the decrease was not as large as in either of the Prednisone delayed-release dose subgroups.

Recurrence of Stiffness During the Day

[0140] In about 58% of the subjects in both treatment groups, recurrence of stiffness during the day was reported at baseline. After two weeks of treatment, the percentage was slightly lower in both treatment groups; after six weeks of treatment, the percentages were notably lower in both treatment groups with no major difference between the treatments; after 12 weeks of treatment, the percentage of subjects concerned was again notably lower compared to the 6-week value in both treatment groups.

Secondary Efficacy Variables.

[0141]

TABLE-US-00006 TABLE 6 Intensity of pain (VAS) after 12 weeks of treatment (intention-to-treat population) Intensity of Prednisone Prednisone pain (VAS) delayed-release Standard (mean (SD)) (N = 144) (N = 144) Baseline [mm] 50.9 (15.2) 52.3 (17.2) (N = 141) (N = 143) At Week 12 (Final 45.7 (24.1) 45.1 (23.1) week) [mm] (N = 142) (N = 144) Relative change [%] −8.57 (55.0) −6.53 (83.9) (N = 141) (N = 143)

[0142] According to the relative changes, the intensity of pain (VAS) was improved after 12 weeks of treatment by both treatments. In the ITT set, the treatment difference in the relative change in intensity of pain (VAS) was calculated to be 4.91% (SD 8.08%). A difference between the 2 groups in favour of Prednisone delayed-release has been observed, which was much more pronounced in the per-protocol set (−19% for Prednisone delayed-release vs-5% for Prednisone standard). The mean number of days with analgesics per week did not change notably after treatment start in both treatment groups. There is no difference between the two treatment groups after 2, 6, and 12 weeks of treatment. However, as under Prednisone delayed-release the intensity of pain went down it can be assumed that in patients with early RA or under long-term treatment also a reduction of painkillers will be seen.

[0143] No differences were observed in all other efficacy variables as listed in the following.

Quality of Sleep

[0144] The mean daily quality of sleep (VAS) did not improve in both treatment groups. There were no marked differences between baseline of the two treatment groups and the means of absolute changes after 2, 6, and 12 weeks of treatment.

Disease Activity Score (DAS 28)

[0145] The Disease Activity Score (DAS 28) decreased in both treatment groups. After two weeks of treatment, the decreases were small, whereas after six and 12 weeks of treatment the decreases were more pronounced. Absolute and relative changes were similar between the two treatment groups after 2, 6, and 12 weeks of treatment.

Tender and Swollen Joint Count

[0146] The tender and swollen joint count decreased in both treatment groups. After two weeks of treatment, the decreases were notable and further decreases were observed in both treatment groups after six and 12 weeks of treatment.

Subject's Global Assessment of Disease Activity

[0147] The mean subject's global assessment of disease activity (VAS) decreased in both treatment groups after start of the treatment with no relevant differences between timepoints and treatments.

Health Assessment Questionnaire Disability Index (HAQ-DI) and Quality of Life (SF36)

[0148] The HAQ-D1 and SF36 scores were similar in both treatment groups at baseline as well as after 12 weeks of treatment.

Physician's Global Assessment of Disease Activity

[0149] In both treatment groups, the number and percentage of subjects whose disease activity was assessed by the physician as mild increased during the course of the treatment; the number and percentage of subjects whose disease activity was assessed by the physician as severe decreased.

Inflammatory Signs

[0150] The mean values of the inflammatory signs CRP and IL-6 at baseline as well as after 2, 6 and 12 weeks of treatment and the respective relative changes are presented in Table 7.

TABLE-US-00007 TABLE 7 Inflammatory signs (CRP, IL-6) (intention-to-treat population) Inflammatory signs (median (min, max)) Prednisone delayed release Prednisone Standard CRP [mg/L] Baseline (Visit 2) 9.9 (1.0, 105.1) 12.2 (1.0, 177.5) At Week 2 (Visit 3) 10.2 (1.0, 159.0) 11.2 (1.0, 106.3) Relative change [%] 13.0 (−96.1, 543.2) 0.0 (−93.1, 1535.4) At Week 6 (Visit 4) 9.9 (1.0, 90.3) 10.7 (1.0, 152.5) Relative change [%] 8.0 (−93.4, 695.2) 0.0 (−94.2, 2377.8) At Week 12 (Visit 5*) 9.1 (1.0, 185.0) 11.5 (1.0, 145.3) Relative change [%] 2.4 (−98.2, 1419.6) 0.0 (−93.0, 2605.6) IL-6 [IU/L] Baseline (Visit 1) 860 (200, 23000) 1110 (200, 20800) At Week 12 (Visit 5*) 470 (200, 9530) 1080 (200, 22700) Absolute change −160 (−13460, 9080) 0.0 (−16190, 18100) Relative change [%] −28.6 (−96.8, 2018) 0.0 (−98.1, 3017)

[0151] The median CRP values did not change notably during the 12-week treatment in both treatment groups.

[0152] IL-6 values decreased during the 12-week treatment in the Prednisone delayed-release treatment group, but remained unchanged in the prednisone standard treatment group. Median values seem to have been halved by the Prednisone delayed-release preparation and the overall range was much smaller after 12 weeks of treatment. The variability was very high in both groups. However, the change under Prednisone delayed-release from baseline to 12 weeks was significantly lower (p<0.001). Also, there was a statistically significant difference between the two treatment groups after 12 weeks.

Osteocalcin

[0153] Osteocalcin is a sensitive measure to the bone metabolism (Heshmati 1998). The mean osteocalcin values at baseline (screening) as well as after 12 weeks of treatment and the respective relative changes are presented in Table 8.

TABLE-US-00008 TABLE 8 Osteocalcin (intention-to-treat population) Osteocalcin [ng/mL] (mean (SD)) Prednisone delayed-release Prednisone Standard Baseline (Visit 1) 20.95 (11.31) 20.04 (9.95) At Week 12 (Visit 5*) 20.40 (12.82) 19.43 (9.49) Relative change [%] −1.7 (33.0) 3.9 (46.4)

[0154] There were no differences between baseline and endpoints or between the two treatments. Thus, it can be concluded that night-time administration of low dose prednisone does not have a negative impact on bone metabolism and risk of osteoporosis.

Continued Efficacy Over During 9 Month Open Follow Up

[0155] Out of 288 patients enrolled into the double blind treatment period, a total of 249 subjects entered the open follow-up phase of the study, 219 subjects completed this phase (see Table 9).

TABLE-US-00009 TABLE 9 Disposition of Subjects Number of subjects Criterion n (%) Enrolled into double-blind phase 288 Enrolled in open follow-up 249 (100) Withdrawn 30 (12.0*) Who completed open follow-up 219 (88.0*)

[0156] Although efficacy was not the main objective of this open follow-up study, the order of reporting was kept the same as in the previous study report on the double-blind phase. In the open follow-up phase the interpretation of the efficacy data was focused on the following three aspects: [0157] maintenance of the effects on stiffness duration achieved by prednisone delayed-release during the double-blind phase in the former prednisone delayed-release group [0158] reduction of morning stiffness to the same extent in the subjects of the former prednisone standard group after three months of treatment with prednisone delayed-release at Visit 6 [0159] further reduction of morning stiffness in the study population after Visit 6 up to 9 months (Visit 8) or after 12 months of treatment with prednisone delayed-release, respectively.

Mean Daily Duration of Morning Stiffness

[0160] The mean daily duration of morning stiffness at start of the double-blind period (Visit 2), at start of the open follow-up period (Visit 5) and at end of study (Visit 8) as well as the relative changes are presented in Table 10 and FIG. 2 for the study population.

TABLE-US-00010 TABLE 10 Mean Daily Duration of Morning Stiffness at Month 9 of Follow-Up (Visit 8) Number of subjects Duration of morning mean (SD) mean (SD) mean (SD) stiffness [min] median (min; max) median (min; max) median (min; max) Visit 2 (Start of Double- 156.27 (97.25) 182.40 (127.43) 169.80 (114.38) blind Period) 137.14 (41.43; 659.29) 149.29 (32.14; 720.0) 143.21 (32.14; 720.0) (n = 107) (n = 115) (n = 222) Visit 5 (Start of Follow- 98.20 (100.22) 150.31 (139.48) 125.56 (124.92) up Period) 75.36 (0.0; 470.0) 116.07 (0.0; 720.0) 83.93 (0.0; 720.0) (n = 114) (n = 126) (n = 240) Relative change [%] −34.47 (68.99) −1.44 (93.07) −17.10 (83.99) to Visit 2 −37.29 (−100.00; 433.53) −19.05 (−100.00; 609.86) −28.75 (−100.00; 609.86) (n = 101) (n = 112) (n = 213) Visit 8* (Month 9 of 73.43 (92.32) 92.88 (124.59) 83.63 (110.60) Follow-up) 42.14 (0.0; 502.5) 60.0 (0.0; 720.0) 46.43 (0.0; 720.0) Relative change [%] (n = 97) (n = 107) (n = 204) to Visit 2 −55.07 (44.79) −44.90 (63.73) −49.71 (55.67) −63.13 (−100; 133.33) −62.96 (−100; 269.44) −63.02 (−100; 269.44) (n = 87) (n = 97) (n = 184) Relative change [%] −7.81 (144.62) −13.90 (146.98) −11.22 (145.56) to Visit 5 −38.33 (−100; 783.75) −40.70 (−100; 950) −40.70 (−100; 950) (n = 78) (n = 99) (n = 177) *Incl. premature termination

[0161] Starting treatment with prednisone delayed-release with longer stiffness duration at Visit 5, the former prednisone standard group achieved almost identical reduction, when percent relative change is calculated from Visit 8 to Visit 5 or from Visit 8 to Visit 2. For all subjects of the study population in the follow-up phase, a further mean reduction of 11.22% (Visit 8 compared to Visit 5) was gained. The total reduction of stiffness duration by 49.71% was observed on long term treatment between Visit 2 and 8.

Mean Daily Duration of Morning Stiffness after Start of Treatment with Prednisone Delayed-Release (Visit 2/Visit 5)

[0162] The mean daily duration of morning stiffness at start of the double-blind period (Visit 2) as well as at start of the follow-up period (Visit 5) and after 3, 6, 9, and 12 months (3-month intervals) of prednisone delayed-release treatment including respective relative changes are presented in Table 11.

TABLE-US-00011 TABLE 11 Mean Daily Duration of Morning Stiffness after Start of Treatment with Prednisone delayed-release (Visit 2/Visit 5) Number of subjects Prednisone Prednisone delayed-release Standard Total Mean daily duration of morning (N = 249) (N = 249) (N = 249) stiffness mean (SD) mean (SD) mean (SD) Visit 2 (Start of Double-blind Period) [min] 156.27 (97.25) — 153.04 (121.71) (n = 107) (n = 233) Visit 5 (Start of Follow-up Period) [min] — 150.31 (139.48) (n = 126) after 3 months of Prednisone delayed- 98.20 (100.22) 85.17 (112.45) 91.92 (106.25) release treatment [min] (n = 114) (n = 106) (n = 220) Relative change [%] −34.47 (68.99) −46.06 (46.86) −40.18 (59.27) (n = 101) (n = 98) (n = 199) after 6 months of Prednisone delayed- 65.70 (100.95) 81.08 (104.79) 74.08 (103.10) release treatment [min] (n = 96) (n = 115) (n = 211) Relative change [%] −56.06 (54.20) −32.83 (116.64) −43.13 (94.71) (n = 86) (n = 108) (n = 194) after 9 months of Prednisone delayed- 62.43 (87.49) 92.88 (124.59) 78.10 (108.99) release treatment* [min] (n = 101) (n = 107) (n = 208) Relative change [%] −61.35 (45.67) −13.90 (146.98) −36.23 (113.67) (n = 88) (n = 99) (n = 187) after 12 months of Prednisone delayed- 73.43 (92.32) release treatment* [min] (n = 97) Relative change [%] −55.07 (44.79) (n = 87) Relative changes refer to values given in bold case *Incl. premature termination

[0163] In Table 11 the duration of morning stiffness is presented as treatment duration of prednisone delayed-release independent from Visits. Relative changes were calculated from the data at Visit 2 for the former prednisone delayed-release group and from the data of Visit 5 for the former prednisone standard group. Taking advantage of the higher number of available data, the interpretation of the results was carried out for the total numbers.

[0164] Before starting with the treatment of prednisone delayed-release the mean daily duration of morning stiffness was 153 min. After three months of treatment stiffness duration was reduced to a mean of 92 min and after six months further to 74 min. After nine months of prednisone delayed-release treatment mean daily duration of morning stiffness was 78 min. For the subjects of the former prednisone delayed-release group data were also available after 12 months of prednisone delayed-release treatment. For these subjects stiffness duration was similar to those after six and nine months of treatment (73 min). No weaning of effects was observed. Thus, the mean duration of morning stiffness was reduced to the half after six months of prednisone delayed-release treatment.

Inflammatory Signs

[0165] The median values of the inflammatory signs CRP and IL-6 during the open follow-up period (Visit 5 to Visit 8) and the respective absolute changes are presented in Table 12 and FIG. 3.

TABLE-US-00012 TABLE 12 Inflammatory Signs (CRP, IL-6) Number of subjects Prednisone Prednisone delayed-release Standard Total (N =120) (N =129) (N =249) median median median Inflammatory signs (min; max) (min; max) (min; max) CRP* [mg/L] Visit 5 (Start of Follow-up) 8.60 (n = 120) 10.90 (n = 129) 9.40 (n = 249) (1.00; 139.80) (1.00; 145.30) (1.00; 145.30) Visit 6 (Month 3 of Follow-up) 8.55 (n = 108) 8.15 (n = 118) 8.35 (n = 226) (1.00; 81.40) (1.00; 152.40) (1.00; 152.40) Absolute change −0.45 (n = 108) −1.20 (n = 118) −0.70 (n = 226) (−131.20; 77.70) (−123.20; 95.00) −131.20; 95.00) Visit 7 (Month 6 of Follow−up) 7.00 (n = 109) 9.05 (n = 118) 8.00 (n = 227) (1.00; 71.00) (1.00; 69.70) (1.00; 71.00) Absolute change −0.60 (n = 109) −0.95 (n = 118) −0.80 (n = 227) (−122.60; 49.00) (−108.10; 25.80) (−122.60; 49.00) Visit 8*** (Month 9 of Follow−up) 8.40 (n = 112) 8.35 (n = 124) 8.35 (n = 236) (1.00; 83.30) (1.00; 86.50) (1.00; 86.50) Absolute change −0.25 (n = 112) −0.25 (n = 124) −0.25 (n = 236) (−129.10; 68.30) (−76.90; 68.70) (−129.10; 68.70) IL-6** [IU/L] Visit 5 (Start of Follow-up) 460 (n = 120) 1050 (n = 127) 710 (n = 247) (200; 9530) (200; 22700) (200; 22700) Visit 8*** (Month 9 of Follow-up) 510 (n = 111) 570 (n = 123) 525 (n = 234) (200; 18300) (200; 8100) (200; 18300) Absolute change 0 (n = 111) −300 (n = 121) −45 (n = 232) (−6830; 16110) (−20600; 6270) (−20600; 16110) *Values <1.0 mg/L were set to 1.0 for analysis **Values <200 IU/L were set to 200 for analysis ***Incl. premature termination.

[0166] The median CRP values did not change notably during the nine months of open follow-up treatment with prednisone delayed-release, except in the former prednisone standard group at Visit 6 where the CRP value was decreased most compared to Visit 5.

[0167] As the variability of the IL-6 values was high in both groups, the median was chosen for comparison rather than the mean values. IL-6 values decreased notably in the former prednisone standard group from 1050 IU/L to 570 IU/L. Thus, IL-6 concentrations were halved in the subjects of the former standard group. This decrease of IL-6 was similar to the decrease of IL-6 in the prednisone delayed-release group described in the double-blind phase. No further reduction was observed in the subjects of the former prednisone delayed-release group.

Overview of Safety

[0168] The safety profile of glucocorticoids in the treatment of rheumatoid arthritis (RA) is well established). The main side effects consist of osteoporosis leading to fractures, gastrointestinal disorders, cardiovascular disorders, increased risk of infections, hyperglycemia, suppression of the HPA axis, and opthalmologic disorders. It is accepted that many of these side effects are observed at high or medium doses but not at low doses (Bijlsma et al. 2003, Bijlsma et al. 2005, Boers 2004, Buttgereit et al 2005, Conn 2001, Da Silva et al. 2005, Saag et al. 1994).

[0169] Prednisone delayed-release is intended for the treatment of RA at low doses (3 to 10 mg prednisone/day) and contains the same active drug ingredient as standard low-dose IR products. Prednisone delayed-release differs from standard products solely with respect to the recommended time of administration and timepoint of drug release within the gastrointestinal tract. The safety profile of low-dose prednisone is well established and reflected in labeling for standard IR products. Clinically significant differences are not expected.

[0170] Brief summary of Adverse Events in Phase III trial under Prednisone delayed-release

[0171] In this study, 59 (41.0%) subjects of the Prednisone delayed-release treatment group and 59 (41.0%) subjects of the prednisone standard treatment group experienced at least one treatment-emergent Adverse Event (AE). A total of 35 subjects (12.2%) experienced AEs that were considered by the investigator to be related to prednisone. AEs causing discontinuation of prednisone were experienced by 22 subjects (7.6%).

[0172] One subject receiving prednisone standard died on study within 18 days after first dose of prednisone. Seven subjects (2.4%) experienced SAEs, and in one subject of these 7 subjects, the SAE was judged to be related to prednisone by the investigator.

[0173] Table 13 summarizes the number of subjects experiencing AEs by type of AE (MedDRA Preferred Term, in at least 1.0% of the treated group).

TABLE-US-00013 TABLE 13 Most common AEs and drug-related AEs in study 003 No. (%) subjects with AE Prednisone Standard delayed-release Prednisone Total Preferred Term (N = 144) (N = 144) (N = 288) All AEs 59 (41.0) 59 (41.0) 118 (41.0) Rheumatoid arthritis 11 (7.6) 13 (9.0) 24 (8.3) Abdominal pain 5 (3.5) 8 (5.6) 13 (4.5) Upper Nasopharyngitis 4 (2.8) 8 (5.6) 12 (4.2) Headache 6 (4.2) 4 (2.8) 10 (3.5) Flushing 4 (2.8) 6 (4.2) 10 (3.5) Nausea 5 (3.5) 4 (2.8) 9 (3.1) Drug-related AEs 19 (13.2) 16 (11.1) 35 (12.2) Abdominal pain 3 (2.1) 4 (2.8) 7 (2.4) Upper Nausea 3 (2.1) 3 (2.1) 6 (2.1) Headache 4 (2.8) 2 (1.4) 6 (2.1) Rheumatoid arthritis 1 (0.7) 4 (2.8) 5 (1.7)

[0174] The most frequently reported AEs (frequency >1.0% of the subjects of the safety set) by MedDRA Preferred Term were rheumatoid arthritis including several terms for worsening (deterioration, escalation, exacerbation, flare etc.) (24 subjects, 8.3%), abdominal pain upper (13 subjects, 4.5%) and nasopharyngitis (12 subjects, 4.2%). The incidences of these AEs were similar in treatment groups.

[0175] During the 9 month open follow-up period, 127 subjects (51.0%) experienced at least one treatment-emergent adverse event (AE). A total of 27 subjects (10.8%) experienced AEs that were by the investigator to be related to prednisone delayed-release. AEs causing discontinuation of prednisone delayed-release were experienced by 13 subjects (5.2%); 68 subjects (27.3%) had AEs not known to be recovered at the end of the study.

[0176] Table 14 summarizes the most common AEs by type of AE (MedDRA Preferred Term, in more than 2% of the subjects).

TABLE-US-00014 TABLE 14 Most Common Adverse Events (Frequency >1.0% Overall) Total (N = 249) Adverse Event (preferred term) n (%) Rheumatoid arthritis 36 (14.5) Flushing 13 (5.2) Upper respiratory tract infection 7 (2.8) Weight increased 7 (2.8) Back pain 7 (2.8) Bronchitis 6 (2.4) Hypercholesterolemia 6 (2.4) Arthralgia 6 (2.4) Nasopharyngitis 6 (2.4) Feeling hot 5 (2.0)

[0177] The most frequently reported AEs (MedDRA Preferred Term) were rheumatoid arthritis (36 subjects, 14.5%) and flushing (13 subjects, 5.2%). Flushing was only reported by the subjects who participated in the CRH testing. Upper respiratory tract infection, increased weight, or back pain were reported less frequently (seven subjects (2.8%) in each case).

Benefits and Risks Conclusions

[0178] Prednisone delayed-release is a novel, delayed-release tablet that has been developed to optimize the efficacy of orally administered low-dose prednisone in the treatment of RA. Prednisone delayed-release has shown improved efficacy compared to standard prednisone in patients with RA without increasing their prednisone dose. This improvement has been solely obtained as a result of Prednisone delayed-release's unique release characteristics. The safety profiles of Prednisone delayed-release and standard prednisone were comparable and the patients were thus not exposed to an increased risk.

[0179] The benefits and main features of Prednisone delayed-release can be summarized as follows:

[0180] A significant reduction of morning stiffness was obtained in patients with long-standing RA who were pretreated with prednisone and DMARDs. A decrease of 10% compared to baseline was already apparent at week 2 of treatment. Under continued treatment this reduction increased in magnitude and plateaued at about 30% to 40% from week 7 onwards. In 50% of the patients (median values), the duration of morning stiffness was reduced by at least one third (33.9%) during the double blind treatment phase. At the end of the 9 month open label follow-up period, a decrease in the duration of morning stiffness of 49% compared to baseline was observed (mean baseline duration of morning stiffness was 3 hours). Morning stiffness is one of the most distressing symptoms for RA patients and thus the observed sustained reduction for at least 12 months under Prednisone delayed-release can be considered a clinically meaningful improvement.

[0181] Both in the double blind and the 9 month open follow-up period, the reduction in morning stiffness was accompanied by a sustained parallel decrease in the pro-inflammatory cytokine IL-6, thus confirming the proposed pharmacological rationale for adapting the timing of prednisone administration to the circadian rhythm of RA.

[0182] These results are surprising because it could not be expected from former investigations (Karatay 2002). Also the long lasting effect of prednisone delayed-release over 12 months on reducing IL-6 levels is unexpected. Further, the long term correlation of IL-6 reduction and morning stiffness reduction could not be expected from former investigations.

[0183] Maximum plasma levels of prednisone in the early morning hours are obtained by administration of Prednisone delayed-release at about 22:00 which is an acceptable time for the patient.

[0184] Prednisone delayed-release tablets can be used in patients with severe, moderate or mild disease.

[0185] Prednisone delayed-release tablets can be used in patients with short, mid-term or long-lasting disease duration.

[0186] Prednisone delayed-release tablets can be used in patients pre-treated with corticosteroids, in those who are refractory to treatment or in corticoid naive patients.

[0187] Prednisone delayed-release tablets can be used as monotherapy or more likely in combination with DMARDs, NSAIDs, TNF a Inhibitors and/or analgetics.

[0188] Prednisone delayed-release tablets can be used for short, mid or long-term treatment.

LITERATURE REFERENCES

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