Publications

Inhibition Préférentielle de JAK1 Par Rapport à JAK3 par l'Upadacitinib : Analyses Exposition-Réponse des Données Ex Vivo de 2 Essais Cliniques de Phase 1 et Comparaison Avec le Tofacitinib

Pharmacodynamics. 2020

Mohamed MF,

Beck D,

Camp HS,

Othman AA

Ex vivo pharmacodynamic assay results demonstrated a greater selectivity of UPA on JAK1 versus JAK3 compared to TOF. This analysis conducted ex vivo stimulation of STAT3 phosphorylation by IL-6 as a measure of JAK1 activity and STAT5 phosphorylation by IL-7 as a measure of JAK1/JAK3 activity. Change in pSTAT3 and pSTAT5 were calculated at 1, 6 and 12 hours following drug administration using samples collected from healthy subjects and subjects with RA, from 2 phase 1 studies. Exposure-response m...

Keywords:

• JAK,
• Upadacitinib,
• Tofacitinib,
• Phase 1,
• Malignancy

Two-Year Safety and Effectiveness of Peficitinib in Moderate-To-Severe Rheumatoid Arthritis: A Phase IIb, Open-Label Extension Study

Rheumatol Ther . 2019 Dec;6(4):503-520. doi: 10.1007/s40744-019-00167-6. Epub 2019 Aug 13.

Genovese MC,

Greenwald MW,

Gutierrez-Ureña SR

Peficitinib (PEF) 100 mg QD demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA in a two-year extension of two global phase IIb studies. Patients enrolled in the LTE had completed one of two 12-week phase IIb PEF trials, one with MTX and one without. The primary objective of the LTE was to assess treatment-emergent adverse events and clinical laboratory evaluations for 105 weeks. As a secondary objective, an additional 2-years of effectiveness ...

Keywords:

• JAK,
• Peficitinib,
• Phase 2,
• LTE

Eficácia e Segurança de Peficitinib (ASP015K) em Pacientes com Artrite Reumatoide com Resposta Inadequada a Metotrexate: Resultados de um Estudo Fase III Randomizado, Duplo-Cego, controlado com Placebo (RAJ4) no Japão

Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215164

Takeuchi T,

Tanaka Y,

Tanaka S,

Kawakami A,

Iwasaki M,

Katayama K,

Rokuda M,

Izutsu H,

Ushijima S,

Kaneko Y,

Shiomi T,

Yamada E,

van der Heijde D

Peficitinib (PEF) 100 and 150 mg demonstrated robust clinical and structural efficacy in patients with RA who have an inadequate response to MTX. In Japan, two JAK inhibitors, TOF and BARI are currently available for RA patients with an inadequate response to conventional therapies. This randomized phase 3 study (RAJ4), assessed the efficacy and safety of two PEF doses in combination with MTX compared to PBO, in Japanese MTX-IR. Patients were randomized 1:1:1 to PBO, PEF 100 mg and 150 mg with M...

Keywords:

• JAK,
• Peficitinib,
• Phase 3

Eficácia e Modelagem Farmacodinâmica do Inibidor de BTK Evobrutinibem Modelos de Doenças Autoimunes

J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583

Haselmayer P,

Camps M,

Liu-Bujalski L,

Nguyen N,

Morandi F,

Head J,

O’Mahony A,

Zimmerli SC,

Bruns L,

Bender AT,

Schroeder P,

Grenningloh

BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evobru...

Keywords:

• BTK,
• Evobrutinib,
• Preclinical

Tuberculose, Hepatite B e Herpes Zoster em Pacientes Tratados com Tofacitinib com Artrite Reumatóide

Immunotherapy. 2019 Mar;11(4):321-333.

Zhang Z,

Deng W,

Wu Q,

Sun L

The risk of TB and hepatitis B virus (HBV) appears to be no greater with TOF than with bDMARDs. Most cases of TB during TOF studies occurred in regions with high background rate of TB, including east Asian countries. TOF is also associated with a higher rate of herpes zoster (HZ) compared with bDMARDs. DMARDs used to treat RA can increase the risk of infections by causing a degree of immunosuppression. A range of bacterial and viral infections have been observed in association with DMARD therapy...

Keywords:

• JAK,
• Tofacitinib,
• Infections

Comparações da Replicação Viral da Hepatite C em Pacientes com Artrite Reumatóide Recebendo Tocilizumabe, Abatacepte e Terapia com Tofacitinibe

Ann Rheum Dis. 2019 Jun;78(6):849-850.

Chen YM,

Huang WN,

Liao TL,

Chen JP,

Yang SS,

Chen HH,

Hsieh TY,

Hung WT,

Chen YH,

Chen DY

Tocilizumab (TCZ), abatacept (ABA) and tofacitinib (TOF) appear to have no major safety concerns for treatment of RA patients with hepatitis C virus (HCV) infections.HCV is an infectious disease which continues to present a major therapeutic challenge for clinicians in treating patients with RA. Previous reports demonstrate that the use of TNF targeted therapies in RA patients with HCV infections appear to have no major safety concerns. During short-term therapy with TCZ and ABA, data has shown ...

Keywords:

• Tofacitinib,
• Tocilizumab,
• Abatacept,
• Infections

Two Years of Sarilumab in Patients with Rheumatoid Arthritis and an Inadequate Response to MTX: Safety, Efficacy and Radiographic Outcomes

Rheumatology 2018;57:1423–1431 DOI: 10.1093/rheumatology/key121

Genovese MC,

van Adelsberg J,

Fan C,

Graham NMH,

van Hoogstraten H,

Parrino J,

Mangan EK,

Spindler A,

Huizinga TWJ,

van der Heijde D,

for the EXTEND study investigators

Two-year treatment of active, moderate-to-severe RA with sarilumab, along with dose reduction in the event of laboratory abnormalities, resulted in durable efficacy outcomes and a safety profile consistent with previous reports involving IL-6R inhibition. Durable long-term safety and efficacy, reduced joint damage progression, and conserving health-related quality of life and work productivity are important goals of therapy in RA.1 Sarilumab significantly reduced disease activity, improved physi...

Keywords:

• IL-6,
• Sarilumab,
• Phase 3,
• Safety,
• Radiographic

Pharmacokinetics of Upadacitinib with Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Clin Pharmacol Drug Dev. 2019 Feb;8(2):208-216. doi: 10.1002/cpdd.462

Mohamed MEF,

Zeng J,

Marroum PJ,

Song IH,

Othman AA

Upadacitinib (UPA) extended release (ER) formulation dosing achieved the target profile that enables single dosing in patients with RA. In early clinical studies, UPA was given as an immediate release (IR) formulation, however patients were noted to experience fluctuations in blood plasma concentrations. To enhance patient compliance in UPA Phase 3 trials, ER tablets have been developed. Here, authors aimed at characterising the pharmacokinetics of UPA single and multiple doses of ER compared wi...

Keywords:

• JAK,
• Upadacitinib,
• PK/PD

Tapering versus Steady-state Methotrexate in Combination with Tocilizumab for Rheumatoid Arthritis: a Randomised, Double-blind Trial

Rheumatology (Oxford) 2018;57(1):84–91

Edwards CJ,

Ӧstӧr AJK,

Naisbett-Groet B,

Kiely P

Methotrexate (MTX) tapering in patients with active, severe RA receiving intravenous tocilizumab (TCZ) was non-inferior to continuing stable MTX doses in maintaining a good/moderate EULAR response. Although MTX and bDMARD combination therapy may produce better response rates than bDMARD monotherapy, one third of patients discontinue or are non-compliant with MTX due to preference or toxicity. This randomised, non-inferiority study investigated the efficacy and tolerability of MTX tapering and ma...

Patient-Reported Outcomes in Newly Diagnosed Early Rheumatoid Arthritis Patients Treated to Target with a Tocilizumab- or Methotrexate-based Strategy

Rheumatology (Oxford) 2017 Dec 1;56(12):2179-2189 doi: 10.1093/rheumatology/kex319

Teitsma XM,

Jacobs JWG,

Welsing PMJ,

Pethö-Schramm A,

Borm MEA,

Hendriks L,

Denissen NHAM,

van Laar JM,

Lafeber FPJG,

Bijlsma JWJ

Patient-reported outcomes (PROs) vastly improved in the first 24 weeks post-initiation of tocilizumab (TCZ) therapies compared to methotrexate (MTX) monotherapy in the U-Act-Early trial.U-Act-Early was a two-year, treat-to-target study that compared the safety and efficacy of TCZ and MTX treatment strategies in DMARD-naïve patients with early RA. Sustained remission was classed as more effective in patients given TCZ monotherapy or combination therapy with MTX compared to MTX alone. TCZ therapie...