Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

• the present invention relates to the medical use of the compound of the invention according to formula I for the treatment of Psoriatic Arthritis (PsA).
• PsA Psoriatic Arthritis
• the present invention also provides methods for the treatment and/or prophylaxis of PsA by administering the compound of the invention according to formula I.
• Psoriatic arthritis is an inflammatory form of arthritis, affecting up to 30 percent of psoriasis patients. Psoriatic arthritis can cause swelling, stiffness and pain in and around the joints, cause nail changes and overall fatigue. Studies show that delaying treatment for psoriatic arthritis as little as six months can result in permanent joint damage. Early recognition, diagnosis and treatment of psoriatic arthritis are critical to relieve pain and inflammation and help prevent joint damage. Despite the availability of a number of treatment options, few current treatments effectively relieve the enthesitis and symptoms in the joints and the skin.
• JAKs are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors.
• JAK family members Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription.
• JAK- STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker et al., 2008).
• JAK1 is a target in the immuno-inflammatory disease area. JAK1 heterodimerizes with the other JAKs to transduce cytokine- driven pro-inflammatory signaling. Therefore, inhibition of JAK1 is of interest for immuno-inflammatory diseases with pathology-associated cytokines that use JAK1 signaling, such as IL-6, IL-4, IL-9, IL-15, IL-21, or IFNy, as well as for other diseases driven by JAK-mediated signal transduction.
• pathology-associated cytokines such as IL-6, IL-4, IL-9, IL-15, IL-21, or IFNy
• Compound I is a potent and selective inhibitor of JAK1, for the treatment of inflammatory disorders.
• Compound I is highly selective for inhibition of JAK1 among 451 unique kinase gene products tested in vitro.
• cytokine-induced STAT1 phosphorylation was inhibited by compound I with half maximal inhibitory concentration (IC50) values of 629 nM and 17,453 nM for JAK1 and JAK2-mediated signaling, respectively, demonstrating 27-fold selectivity for JAK1 over JAK2 in this assay.
• IC50 half maximal inhibitory concentration
• JAK inhibitors are evaluated for the treatment of PsA.
• a phase III trial in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease modifying antirheumatic drugs, being administered tofacitinib showed an ACR20 response rate at month 3 of 50% dosed at 5mg and 61% dosed at lOmg compared to 33% in the placebo group (Mease P. et al NEJM 377;l6 1537-1550).
• JAK inhibitors are useful and effective molecules in the treatment of inflammatory conditions
• drawbacks to the use of these compounds have been reported including anemia, thrombocytopenia and neutropenia, hypercholesterolemia, creatinine increase, all of which may result from the lack of selectivity, in particular selectivity against JAK2 (O’Shea, J.J. et al. 2013. Back to the Future: Oral targeted therapy for RA and other autoimmune diseases. Nat. Rev. Rheumatol. 9, 173-182; O’Shea, J.J., Plenge, R., 2012. JAKs and STATs in Immunoregulation and Immune-Mediated Disease. Immunity 36, 542-550).
• JAK inhibition in particular JAK1 may result in safe and effective treatment agent.
• JAK1 Janus kinase inhibitors for rheumatoid arthritis. Curr. Opin. Chem. Biol. 32, 29-33).
• the present invention relates to the finding that compound I has shown its unexpected high potential in treating psoriatic arthritis with a favorable benefit risk profile.
• a Phase Ila trial (reported example 1 herein), an ACR20 of up to 80% following 16 weeks of using compound I in the treatment of patients suffering psoriatic arthritis is shown. Further particular findings will be apparent in the description of the invention below.
• a dose selected from 100 to 200 mg once a day, or 50 to 100 mg twice a day.
• the compound according to formula I is dosed as the sole active agent for the treatment PsA.
• the compound according to formula I for use in the treatment of psoriatic arthritis dosed orally at a dose selected from 100 or 200 mg once a day, or 100 mg twice a day, where a statistically significant ACR20 response is seen following 1 week of treatment.
• the compound according to formula I for use in the treatment of psoriatic arthritis dosed orally at a dose selected from 100 or 200 mg once a day, or 100 mg twice a day, where a statistically significant ACR50 response is seen following 1 week of treatment.
• composition such as a pharmaceutical composition, comprising compound I according to any of the embodiments disclosed herein, and, a pharmaceutically acceptable vehicle.
• a method of treatment of psoriatic arthritis comprising the step of administering a person in need thereof the compound according to formula I orally at a dose selected from 100 or 200 mg once a day, or 100 mg twice a day.
• the method of treatment leads to an ACR20 response in at least 60, 70 or 80% of patients.
• the ACR20 response is statistically significant following 1 week of treatment.
• the method of treatment leads to an ACR50 response in at least 30, 35 or 40% of patients.
• the ACR50 response is statistically significant following 1 week of treatment.
• the patient subjected to the treatment was not previously exposed to bDMARDs, in particular to anti-TNF treatment.
• the patient subjected to the treatment shows signs and/or symptoms of enthesitis.
• the articles‘a’ and‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
• an analogue means one analogue or more than one analogue.
• ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
• ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
• such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, l,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenes
• salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
• pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
• ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
• Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
• Conventional solvents include water, EtOH, acetic acid and the like.
• the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
• Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates ln certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• Solvate encompasses both solution-phase and isolable solvates.
• Representative solvates include hydrates, ethanolates and methanolates.
• Subject includes humans.
• the terms‘human’,‘patient’ and‘subject’ are used interchangeably herein.
• Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
• The“effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
• Preventing refers to a reduction in risk of acquiring or developing a disease or disorder, i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
• prophylaxis is related to‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
• prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
• ‘Treating’ or‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e.
• ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
• ‘treating’ or‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
• “treating” or “treatment” relates to slowing the progression of the disease.
• the terms“ACR20”,“ACR50” and“ACR70” as used herein are scores which indicate how much a patient’s symptoms of peripheral arthritis have improved according to criteria set out by the American College of Rheumatology (ACR).
• the ACR score represents a percentage.
• An ACR20 score means that a person’s arthritis symptoms have improved by 20%
• an ACR50 score means it has improved by 50%
• an ACR70 score means it has improved by 70%.
• a person must have at least 20% fewer tender joints (at least 20% improvement from baseline in tender joint counts, TJC68) and at least 20% fewer swollen joints (at least 20% improvement from baseline in swollen joint counts, SJC66).
• the patient must show a 20% improvement in at least three of the following five areas: the person’s overall (global) assessment of his or her own disease activity (on a 0-100 mm visual analog scale (VAS)), the physician’s global assessment of the person’s disease activity (on a 0-100 mm VAS), the person’s assessment of his or her own PsA pain intensity (on a 0-100 mm VAS), the person’s assessment of his or her own physical functioning as measured by HAQ-DI, and the results of a C-reactive protein (CRP) blood test (in mg/dL or mg/L).
• ACR50 and ACR70 scores use the same criteria but require 50% and 70% improvement, respectively.
• DAS28(CRP) refers to a clinical scoring ranging from 2.0 to 10.0 to measure the disease activity in a patient, and includes a 28 tender and swollen joint count, CRP measurement from blood analysis, and a general health assessment on a VAS. Further details on the determination of DAS28(CRP) is provided in example 1.
• a DAS28(CRP) value below 2.6 is indicative of remission
• a DAS28(CRP) between 2.6 and 3.2 is indicative of low disease activity
• between 3.2 and 5.1 is indicative of moderate disease activity
• a DAS28(CRP) above 5.1 is linked to high disease activity (Wells et al., 2009 Ann. Rheum. Dis. 68,954-960).
• CRP C-Reactive protein in blood serum and is a marker of inflammation.
• guidelines for CRP are widely available, and normal values of ⁇ 0.5 mg/dL are recommended (Porter, 2011 The Merck Manual of Diagnosis and Therapy (Wiley)).
• the term‘enthesitis’ refers to entheseal inflammation which is a typical feature of PsA and is one of the features which distinguishes it from rheumatoid arthritis.
• SPARCC Enthesitis Index refers to a clinical scoring after examination of (entheseal) tenderness at 16 peripheral sites, which are evaluated for tenderness by palpation, and scored 0 (non-tender) or 1 (tender). The total enthesitis score is the sum of all site scores and is maximally 16. The higher the score, the higher the enthesitis burden.
• the term‘Leeds Enthesitis Index’ or‘LET refers to a clinical scoring after examination of (entheseal) tenderness at six sites: 2 sites at each of the lateral epicondyles of the humerus, medial condyles of the femur and the insertion of the Achilles tendon.
• the LEI score range is 0-6. The higher the score, the higher the enthesitis burden.
• HAQ-ID refers to the Health Assessment Questionnaire without Disability Index, which is a measure for the physical functioning of a patient.
• the HAQ-DI is a 20- question instrument assessing the degree of difficulty a person has in accomplishing tasks in 8 function areas (B. Bruce and J. Fries, "The Stanford Health Assessment Questionnaire: dimensions and practical applications," Health Qual Life Outcomes, p. 1 :20, 2003).
• the HAQ-D1 total score ranges from 0 to 3 with higher scores indicating greater dysfunction.
• MDA Minimal Disease Activity
• a patient will be classified as having achieved MDA when 5 out of 7 of the following criteria are met:
• the term ‘PAST refers to the Psoriasis Area and Severity lndex score and is an index used to express the severity of psoriasis ft combines the severity (erythema, induration and desquamation) and percentage of affected area. Further details on the determination of PAS1 is provided in example 1.
• the PAS1 score represents the change from baseline.
• ‘PAS150’ refers to the portion of patients who achieved 50% improvement in the PAS1 score upon the tested treatment.
• ‘PAS175’ refers to the portion of patients who achieved 75% improvement in the PAS1 score upon the tested treatment.
• PAS190’ refers to the portion of patients who achieved 90% improvement in the PAS1 score upon the tested treatment.
• BSA refers to the body surface area and is an estimation of the percentage of the body affected by psoriasis. BSA ⁇ 3% is scored mild case of psoriasis, BSA of 3-10% is scored as a moderate case of psoriasis, and BSA >10% is scored as a severe case of psoriasis.
• cDMARD refers to conventional disease modifying anti rheumatic drugs.
• cDMARD are synthetic drug also referred to as conventional synthetic disease modifying anti rheumatic drugs (csDMARD).
• Specific examples of cDMARD for the treatment of psoriatic arthritis include methotrexate, leflunomide, sulfasalazine, chloroquine and hydroxychloroquine.
• bDMARD refers to biological disease modifying anti rheumatic drugs.
• a particular class of bDMARDS are tumor necrosis factor (TNF) inhibitors, also referred to as anti-TNF pharmaceuticals, such as etanercept, adalimumab, infliximab, golimumab, certolizumab or certolizumab pegol.
• TNF tumor necrosis factor
• the term‘TNF-nai ' ve patient’ refers to a patient previously not exposed to an anti-TNF pharmaceutical such as anti-TNF monoclonal antibody treatment or subjects previously exposed to anti-TNF therapy (for example and without limitation infliximab, golimumab, adalimumab, certolizumab and/or certolizumab pegol) at a dose registered for the treatment of inflammatory conditions that has been discontinued at least 8 weeks prior to entering the study.
• an anti-TNF pharmaceutical such as anti-TNF monoclonal antibody treatment or subjects previously exposed to anti-TNF therapy (for example and without limitation infliximab, golimumab, adalimumab, certolizumab and/or certolizumab pegol) at a dose registered for the treatment of inflammatory conditions that has been discontinued at least 8 weeks prior to entering the study.
• the term‘TNF-experienced patient’ refers to a patient that is receiving at the time of entering the study or has received anti-TNF pharmaceutical such as anti-TNF monoclonal antibody treatment (for example and without limitation infliximab, golimumab, adalimumab, certolizumab and/or certolizumab pegol) and is no longer responsive to such treatment.
• anti-TNF pharmaceutical such as anti-TNF monoclonal antibody treatment (for example and without limitation infliximab, golimumab, adalimumab, certolizumab and/or certolizumab pegol) and is no longer responsive to such treatment.
• anti-TNF pharmaceutical refers a class of drugs that are used to treat inflammatory conditions, in particular rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, inflammatory bowel disease (Crohn’s and ulcerative colitis), ankylosing spondylitis and psoriasis.
• TNF is a chemical produced by the immune system that causes inflammation in the body. In healthy individuals, excess TNF in the blood is blocked naturally, but in those inflammatory conditions, higher levels of TNF in the blood lead to more inflammation and persistent symptoms.
• anti-TNF pharmaceutical include infliximab, golimumab, adalimumab, certolizumab and certolizumab pegol. Accordingly, the term“anti-TNF treatment” refers to treatment by means of administering an anti-TNF pharmaceutical.
• treatment effect refers to the effect attributed to a particular or specified treatment, such as treatment of psoriatic arthritis using compound I.
• Psoriatic arthritis is an inflammatory joint disease associated with psoriasis and characterized by heterogeneous musculoskeletal phenotypes that involve multiple domains including the peripheral joints, axial skeleton, tendon and ligament insertion sites (enthesitis) and digits (dactylitis). PsA occurs in approximately 30% of psoriasis patients. In the majority of cases (75%) psoriasis precedes joint disease, but in some cases (15%) the onset is synchronous and in 10% arthritis precedes psoriasis. In the latter, unrecognized psoriasis may be found or there may be a history of widespread guttate psoriasis in childhood or a strong family history.
• PsA occurs just as frequently in males and females.
• the arthritis in PsA commonly involves distal joints and has the tendency to distribute in a ray pattern, so that all the same joints of a single digit are more likely to be affected (dactylitis).
• the degree of erythema over the affected joints, the presence of asymmetrical spinal involvement, the presence of enthesitis and a lower level of tenderness are also typical features of PsA.
• PsA belongs to the group of spondyloarthropathies because of the presence of spondylitis in up to 40% of patients.
• the extra-articular features observed in PsA are similar to other spondyloarthropathies including mucous membrane lesions, ulceris, urethritis, diarrhea and aortic root dilatation, and association with HLA-B27.
• First-line treatment traditionally consists of non-steroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying anti-rheumatic drugs (cDMARDs) such as sulfasalazine (SSZ), methotrexate (MTX) and leflunomide (LEF).
• NSAIDs non-steroidal anti-inflammatory drugs
• cDMARDs conventional disease-modifying anti-rheumatic drugs
• SSZ sulfasalazine
• MTX methotrexate
• LEF leflunomide
• agents with different mechanism of actions that target the interleukin(IL)-23/IL-l7 pathways that promote skin and joint inflammation have become available and more are currently under evaluation in clinical studies.
• These agents include the IL-12/IL-23 inhibitors ustekinumab, and tildrakizumab; the IL-23 inhibitor guselkumab; the IL-17 receptor A inhibitors such as secukinumab and ixekizumab, the IL-17 receptor inhibitor brodalumab, the IL-17 receptor A/F inhibitor bimekizumab and the phosphodiesterase E4 inhibitor apremilast.
• IL-17 blockade is also effective for axial disease and inhibits radiographic progression.
• the oral agent apremilast offers a modest response in the skin and joints, with few safety signals and is not indicated in patients who demonstrate radiographic damage or axial involvement.
• JAK Janus Kinase
• STAT signal transducer and activator of transcription
• the present invention provides the compound of the invention for use in the treatment of psoriatic arthritis, wherein the compound of the inventions is according to formula I:
• a compound of the invention according to any one of the embodiments herein described is present as the free base.
• a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
• the compound of the invention is present as a 1 : 1 maleate salt.
• a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
• a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
• the solvate of a pharmaceutically acceptable salt is a [Compound according to Formula I:H01:3H 2 0] adduct.
• compounds of the invention may be metabolized to yield biologically active metabolites.
• An active metabolite of the compound according to formula I is described in WO2013/189771.
• a compound of the invention is said metabolite of the compound according to Formula I, said metabolite being according to formula II:
• the present invention provides the compound of the invention or pharmaceutical compositions comprising the compound of the invention, for use in the treatment of psoriatic arthritis when dosed orally at a daily dose of between 100 mg to 250 mg, administered in one or two gifts.
• the dose is selected from 50 mg twice per day (b.i.d.), 100 mg once a day (q.d.), 100 mg b.i.d., and 200 mg q.d.
• the patients are not concomitantly treated with another agent or medicine for psoriatic arthritis.
• the patients have had insufficient response to or are intolerant to one or more conventional Disease Modifying AntiRheumatic Drug (cDMARD), such as methotrexate, leflunomide, sulfasalazine and hydrochloroquine or chloroquine.
• cDMARD Disease Modifying AntiRheumatic Drug
• the patients are concomitantly treated with another agent for the treatment of psoriatic arthritis, such as cDMARD therapy, such as treatment with methotrexate (such as up to 25 mg/week orally or parental), leflunomide (such as up to 20 mg/day orally), sulfasalazine (such as 3 g/day orally), hydrochloroquine (such as up to 400 mg/day) or chloroquine (such as up to 250 mg/day).
• methotrexate such as up to 25 mg/week orally or parental
• leflunomide such as up to 20 mg/day orally
• sulfasalazine such as 3 g/day orally
• hydrochloroquine such as up to 400 mg/day
• chloroquine such as up to 250 mg/day
• the patients are naive to treatment with a bDMARD, in particular an anti-TNF pharmaceutical.
• the patients were previously treated with a bDMARD, in particular an anti-TNF pharmaceutical, and in particular, the patients had insufficient or inadequate response to previous treatment using a bDMARD such as an anti-TNF pharmaceutical.
• the compound of the invention is particularly useful for the treatment of a patient having psoriatic arthritis who displays signs and symptoms of enthesitis.
• a patient having psoriatic arthritis who displays signs and symptoms of enthesitis.
• PsA patient suffers enthesitis as determined per SPARCC Enthesitis Index.
• PsA patient suffers enthesitis as determined per Leeds Enthesitis Index (LEI score), e.g. LEI score of more than 0.5 or more than 1.0.
• LEI score e.g. LEI score of more than 0.5 or more than 1.0.
• an ACR20 response is seen in at least 50% of the patient population after 4 weeks of treatment.
• an ACR20 response is seen in at least 55%, at least 60%, of the patient population after 4 weeks of treatment.
• the ACR20 response is seen after 8 weeks of treatment, after 12 weeks of treatment or after 16 weeks of treatment.
• an ACR20 response is seen in at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83% of the patient population after 12 weeks of treatment.
• the ACR20 response of at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83% is seen after 16 weeks of treatment.
• an ACR50 response is seen in at least 30% of the patient population after 12 weeks of treatment.
• an ACR50 response is seen in at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45% of the patient population after 16 weeks of treatment.
• an ACR70 response is seen in at least 10% of the patient population after 12 weeks of treatment. Particularly, an ACR70 response is seen in at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25% of the patient population after 16 weeks of treatment.
• the LEI score is reduced by at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8 or at least 1.9.
• the LEI score is reduced by at least 1.5, more specifically following 16 weeks of treatment, following 12 weeks of treatment, following 8 weeks of treatment or even more specifically following 4 weeks of treatment.
• the HAQ-DI (relating to the physical functioning of the patient) upon treatment using compound I reduces by at least 0.35, at least at least 0.40, at least 0.43, at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least 0.54, at least 0.55, or at least 0.57.
• the HAQ-DI is reduced by at least 0.40 points following 4 weeks of treatment.
• the HAQ-DI is reduced by at least 0.45 points following 12 weeks of treatment.
• the HAQ-DI is reduced by at least 0.45 points following 8 weeks of treatment.
• the HAQ-DI is reduced by at least 0.50 points following 16 weeks of treatment.
• compound I was effective in reducing psoriatic skin manifestations, also referred to as psoriasis. Such effect is assessed and quantified by Psoriasis Area and Severity Index (PASI) (see section 1.5.3).
• PASI Psoriasis Area and Severity Index
• the compound according to formula I is for use in a PsA patient having psoriasis, such as patients with at least 3% of their body surface area covered by psoriasis.
• compound I is used to improve the pruritic component of psoriasis.
• At least 15%, at least 17% or at least 20% of the patients achieved MDA status following 16 weeks of treatment, or more specifically, following 12 weeks of treatment.
• Example 1 Clinical study - treatment of subjects with moderately to severely active psoriatic arthritis (ClinicalTrials.gov Identifier: NCT03101670) a. Purpose of the study
• the primary objective of the study is to evaluate the effect of compound I compared to placebo on psoriatic arthritis as assessed by the ACR20 following 16 weeks of treatment.
• a sufficient number of subjects will be screened to ensure that approximately 124 subjects with moderately to severely PsA will be randomized to compound I 200 mg or matching placebo.
• cDMARD therapy subjects are only permitted to use one of the following drugs and must have been on it for 12 weeks prior to Screening, with a stable dose (including stable route of administration) for at least 4 weeks prior to Baseline:
• Methotrexate oral or parenteral up to 25 mg/week (local standard of care must be observed with regard to concomitant use of folic or folinic acid supplementation);
• Leflunomide up to 20 mg/day orally;
• Hydroxychloroquine up to 400 mg/day or chloroquine up to 250 mg/day.
• opioid analgesics e.g. methadone, hydromorphone, morphine or oxycodone
• alkylating agents e.g. chlorambucil or cyclophosphamide, at any time;
• Adalimumab certolizumab pegol, golimumab: 8 weeks
• Infliximab 12 weeks;
• biologic immunomodulating agents include, but not limited to: cell depleting biologic agents (e.g., anti-CD20, CAMPATH, anti-CD4, anti-CD3), denosumab, anti-IL-6 (e.g. tocilizumab), anti-IL-l7 (e.g. secukinumab, ixekizumab, brodalumab), anti-IL-l2/IL-23 (e.g. ustekimumab), anti- IL-23 (e.g. tildrakizumab, guselkumab), rituximab at any time;
• cell depleting biologic agents e.g., anti-CD20, CAMPATH, anti-CD4, anti-CD3
• denosumab e.g. tocilizumab
• anti-IL-6 e.g. tocilizumab
• anti-IL-l7 e.g. secukinumab, ixekizumab, brodaluma
• Any therapy by intra-articular injections e.g. corticosteroid, hyaluronate
• any therapy by intra-articular injections e.g. corticosteroid, hyaluronate
• NSAID cyclooxygenase-2
• COX-2 cyclooxygenase-2
• Leflunomide if being discontinued less than 12 weeks prior to Baseline or less than 4 weeks prior to Baseline if a washout procedure (e.g. cholestyramine) has been performed;
• a washout procedure e.g. cholestyramine
• any of the following systemic immunomodulating therapies within 4 weeks prior to Screening including but not limited to: 6-mercaptopurine, azathioprine, cyclosporine or other calcineurin inhibitors (e.g. sirolimus, tacrolimus), dapsone, fumaric acid derivatives, gold therapy, MTX if being discontinued, mycophenolate, antimalarials (e.g., hydroxychloroquine, chloroquine) if being discontinued, SSZ if being discontinued, apremilast or thioguanine;
• 6-mercaptopurine e.g. sirolimus, tacrolimus
• dapsone e.g. sirolimus, tacrolimus
• fumaric acid derivatives e.g., gold therapy, MTX if being discontinued, mycophenolate, antimalarials (e.g., hydroxychloroquine, chloroquine) if being discontinued, SSZ if being discontinued,
• Any topical therapies including, but not limited to: alpha or beta hydroxy acids, anthralin, corticosteroids (except mild potency corticosteroids on face, scalp, axillary and genital area), >3% salicylic acid preps, retinoids including tazarotene, tar preps, or urea: 2 weeks;
• P-gp potent P-glycoprotein
• a potent P-glycoprotein inducer e.g. carbamazepine, clotrimazole, cyclosporine, dexamethasone, phenothiazine, phenytoin, retinoic acid, rifampin, St. John’s wort and venlafaxine.
• Potent P-gp inducers require washout of 3 weeks prior to Baseline;
• any generalized musculoskeletal disorder e.g., generalized osteoarthritis, or systemic inflammatory condition other than PsA
• generalized musculoskeletal disorder e.g., generalized osteoarthritis, or systemic inflammatory condition other than PsA
• PsA systemic inflammatory condition other than PsA
• Gout is permitted if subject is well controlled on urate lowering therapy with no evidence of flare of disease in the last year and current uric acid level ⁇ 7.0 mg/dL. Presence of very poor functional status or unable to perform self-care.
• QuantiFERON-TB Gold test result (Note: if QuantiFERON-TB Gold test result is indeterminate, it may be repeated once, and if indeterminate or positive on retest, subject is not eligible) or
• chest radiograph posterior anterior view
• a qualified radiologist or pulmonologist with evidence of current active TB or old inactive TB or
• Subject with newly identified LTBI i.e. a subject who has a newly identified positive diagnostic TB test result (defined as any positive QuantiFERON-TB Gold test or an indeterminate test result on 2 separate QuantiFERON-TB Gold tests) for whom active TB has been ruled out including having a negative chest radiograph, and for whom appropriate treatment for LTBI has been initiated, continued for at least 4 weeks prior to the first study drug administration and if ongoing at Screening is planned to be continued during the study until completed.
• Adequate treatment for LTBI is defined according to United States (US) Centers for Disease Control guidelines. 12.
• HCV hepatitis C virus
• herpes zoster or herpes simplex infection within 12 weeks prior to Screening or have history of disseminated or complicated herpes zoster infection (e.g. multidermatomal, ophthalmic, or CNS involvement) at any time.
• ALT Alanine aminotransferase
• AST aspartate aminotransferase
• Efficacy assessments to estimate signs and symptoms of PsA and peripheral arthritis, psoriasis, enthesitis, dactylitis, spondylitis, and physical function are carried out at Baseline (Day 1) and at Weeks 1, 2, 4, 8, 12, 16, or at the early discontinuation visit (EDV) if applicable, unless otherwise noted.
• the individual components of the ACR response criteria are obtained at screening and throughout the study.
• the subject’s serum CRP are measured using a hsCRP test at the time points indicated in the study flow chart. Post-baseline CRP results are blinded to the investigator and the sponsor until database lock.
• Each of 66 joints will be evaluated for swelling (SJC66) and each of 68 joints for tenderness (TJC68) at time points described in the protocol.
• a joint assessor with adequate training and experience in performing joint assessments is designated at each investigational site to perform all joint assessments.
• the joint assessor is preferably be a rheumatologist; however, if a rheumatologist is not available, it should be a health care worker with at least 1 year experience in performing joint assessments.
• the assessor should remain the same throughout the study per subject, as much as possible. It is required that the designated joint assessor identifies an appropriate back-up assessor to provide coverage if the designated joint assessor is absent.
• the 68 tender joint count should be done by scoring the presence or absence of tenderness as assessed by pressure and joint manipulation on physical examination.
• Enthesitis is assessed using the SPARCC Enthesitis Index. Sixteen body sites is evaluated for tenderness by palpation, and scored with 0 (non-tender) or 1 (tender). The total enthesitis score is the sum of all site scores and is maximally 16. The higher the score, the higher the enthesitis burden.
• medial femoral condyles (left and right) is also assessed and evaluated in a similar way as the other 16 sites to allow assessing the Leeds enthesitis index (LEI).
• Dactylitis is assessed by evaluation of the size and tenderness of all fingers and toes using the LDI.
• the LDI measures the ratio of the circumference of the affected digit to the circumference of the digit on the contra-lateral hand or foot using a Leeds Dactylometer.
• a dactylitic digit is defined by a minimum difference of 10%. If the contralateral digit is also dactylitic, a table of normative values based on population averages is used to provide the comparison. The ratio of circumference is multiplied by a binary tenderness score (0 for non-tender, 1 for tender). The results from each digit with dactylitis are then summed to produce a final score.
• the PASI score is used to measure the severity and extent of psoriasis. Representative area of psoriasis is selected for each body region (head, arms, trunk and legs). The intensity of erythema, induration and desquamation of the psoriasis is assessed as none (0), mild (1), moderate (2), severe (3) or very severe (4).
• a numerical score ranging from 0 to 100%, will be used to measure the proportion of the subject’s total BSA involved with psoriasis, as assessed by the investigator.
• the Physician’s Global Assessment of psoriasis is used to determine the subject’s psoriasis lesions overall at a given time point.
• the subject’s psoriasis disease activity is assessed by a physician, using a 6-point scale (see 1.5.1 below), which ranges from 0 (cleared) to 5 (severe). 1.4.8. Modified Nail Psoriasis Area and Severity Index (mNAPSI)
• the mNAPSI will evaluate the severity of nail matrix psoriasis and nail bed psoriasis (Cassell S. et al. "The modified Nail Psoriasis Severity Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.," J Rheumatol., pp. 34(l):l23-9, 2007).
• Characteristics of nail matrix psoriasis include pitting, leukonychia, red spots in the lunula, and nail plate crumbling.
• Nail bed characteristics affected by psoriasis include oil-drop discoloration, onycholysis, nail bed hyperkeratosis, and splinter hemorrhages.
• Each of the subject’s nails is assessed for presence of any of the nail matrix and nail bed psoriasis features, taking into account the following abnormalities and rules:
• Each finger will have a score between 0 and 14, and the total mNAPSI score ranges from 0 to 140.
• the subject’s global assessment of their arthritis disease activity is recorded on a 0 to 100 mm VAS.
• a perpendicular line is drawn on the VAS, and with a ruler, the distance between the beginning of the line and the mark on the 10-cm line in mm will be the score from 0-100.
• a score of 0 indicates “very well” and 100 indicates“very poor” to the question“Considering all the ways psoriatic arthritis affects you, how well are you doing today?”.
• the Patient’s Global Assessment of psoriasis is a single-item, patient-completed assessment that is used to evaluate the overall extent of psoriasis-related cutaneous disease at a particular point in time using a 5-category scale ranging from“clear” (0 points - no psoriasis) to“severe” (4 points).
• the patient’s assessment of pain is performed using a 0-100 mm VAS ranging from“no pain” to“unbearable pain” after the question“Please indicate with a vertical mark (
• HAQ-DI Health Assessment Questionnaire-Disability Index
• the HAQ-DI is used to monitor the subject’s self-assessed physical function or disability. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 function areas (getting dressed, arising, eating, walking, sleeping, hygiene, reaching, gripping, errands and chores). Responses are scored on a 4-point Likert scale from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The need for aids/devices or help from another person is also recorded. The HAQ-DI total score ranges from 0 to 3 with higher scores indicating greater dysfunction.
• Pruritus NRS Pruritus Numeric Rating Scale
• the subject is, at each study visit, asked to complete an evaluation of pruritus using a visual rating scale with numbered intervals (integers).
• the subject rates the intensity of pruritus based on a recall period of 24 hours of the most severe episode of pruritus experienced during that time interval.
• the subjects are asked to rate their pruritus on a 0 (no itching) to 10 (worst possible itching) scale.
• the FACIT-Fatigue scale (version 4) measures an individual’s level of fatigue during their usual daily activities over the past week. It consists of 13 questions with a 7-day recall period on a 5- point Likert scale, with 0 indicating“not at all” and 4 indicating“very much”. The total score ranges from 0 to 52. The higher the score, the better the quality of life.
• the health-related quality of life of the subject is assessed using the SF-36 (version 2, SF- 36v2® Health Survey) with a 1-week recall period. This consists of 36 questions belonging to 8 domains in 2 components: - Physical well-being: 4 domains: physical functioning (10 items), role physical (4 items), bodily pain (2 items), and general health perceptions (5 items).
• the PsAID questionnaire assesses the impact of PsA on people’s lives.
• the EULAR PsAID questionnaire PsAID9 for clinical trials is used. It is a 9-item questionnaire, where each item is scored between 0 and 10. All items are prioritized according to importance of the health domain it represents. The weight of each domain is taken into account in the total PsAID score. A higher score on the PsAID indicates more impact of the disease. A score below 4 out of 10 is considered a patient-acceptable status. A change of 3 or more points is considered a relevant absolute change.
• the signs and symptoms of peripheral arthritis are measured using ACR20/50/70.
• the ACR response is a measurement of improvement in multiple disease assessment criteria.
• a positive ACR20 response is defined as at least 20% improvement from baseline in both swollen (SJC66) and tender (TJC68) joint counts, and at least 20% improvement in 3 or more of the following 5 criteria:
• a positive ACR50 and ACR70 response is derived from the definition of the ACR20, but requiring at least 50% and 70% improvement, respectively.
• the disease activity in PsA will be measured using the MDA, which is a measure to indicate disease remission.
• the MDA is based on a composite score of 7 domains. A patient will be classified as having achieved MDA when 5 out of 7 of the following criteria are met:
• PASI 0.1 x (Eh + Ih + Dh) x Ah + 0.2 x (Eu + Iu + Du) x Au + 0.3 x (Et + It+ Dt) x At + 0.4 x (El + II + Dl) x A1
• the total PASI score ranges between 0 (no disease) and 72 (maximal disease), but is considered unreliable when BSA ⁇ 3%. Therefore, the PASI is only analysed in the subpopulation of subjects with psoriasis involving >3% BSA at baseline.
• Enthesitis is assessed using the SPARCC Enthesitis Index and Leeds Enthesitis Index (LEI). The Enthesitis parameters are analyzed only in the subpopulation of subjects who have enthesitis at baseline (LEI >0). Analysis focusses on the changes from baseline.
• HAQ-DI is scored on a scale from 0 to 3 and changes from baseline are reported. A decrease by at least 0.22 points versus the baseline is considered clinically meaningful.

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