A pooled analysis of serious infections and herpes zoster-related disease in Asian patients with rheumatoid arthritis treated with peficitinib (ASP015K) over a median of 3 years

ABSTRACT Objective To analyse serious infection (SI) and herpes zoster-related disease (HZD) during long-term treatment of rheumatoid arthritis with the oral Janus kinase inhibitor, peficitinib (ASP015K). Methods This was a post hoc analysis of pooled data from one Phase 2b study and two Phase 3 studies and final data from a long-term extension study of peficitinib in Asian rheumatoid arthritis patients. Two pooled datasets were analysed (Phase 3 studies and Phase 2/3 studies). Univariate and multivariate Cox regression analyses explored relationships between exposure-adjusted incidence rate of SI and HZD, peficitinib dose, and baseline factors. Results Total peficitinib exposure for 1052 patients receiving once-daily peficitinib in the pooled Phase 2/3 Asian studies was 2998.9 patient-years. Exposure-adjusted incidence rates (95% confidence interval) of SI and HZD were 2.7 (2.2, 3.4) and 6.9 (6.0, 8.0) per 100 patient-years, respectively, in pooled Phase 2/3 studies. Advanced age was prognostic for SI and HZD, while baseline prednisolone dose was prognostic for SI. There was no temporal relationship between either adverse event and prolonged peficitinib administration. Conclusions As expected in this peficitinib-treated population, older patients had increased risk of SI and HZD, and those receiving higher prednisolone doses had increased risk of SI.

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Effects of denosumab in Japanese rheumatoid arthritis patients treated with conventional anti-rheumatic drugs: 36-month extension of a phase 3 study

The Journal of Rheumatology ◽

10.3899/jrheum.201376 ◽

2021 ◽

pp. jrheum.201376

Author(s):

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Satoshi Soen ◽

Hisashi Yamanaka ◽

Toshiyuki Yoneda ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Type I Collagen ◽

Joint Destruction ◽

Term Treatment ◽

Drug Discontinuation ◽

Type I ◽

Mineral Density ◽

Phase 3 ◽

Long Term Treatment

Objective To evaluate safety and efficacy of long-term denosumab 60 mg every 6 (Q6M) or 3 months (Q3M) in rheumatoid arthritis (RA) patients. Methods This 12-month, randomised, double-blind, placebo-controlled, multicentre phase 3 trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese RA patients treated with placebo for 12 months then denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M); denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp (mTSS), bone erosion (ES), and joint space narrowing (JSN) scores. Results Long-term treatment better maintained mTSS and ES suppression in the P/Q3M and Q3M/Q3M versus P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS at 36 months were 2.8 (standard error 0.4), 1.7 (0.3), 3.0 (0.4), and 2.4 (0.3), respectively; corresponding changes in ES were 1.3 (0.2), 0.4 (0.2), 1.4 (0.2), and 1.1 (0.2). No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-telopeptide of type I collagen decreased rapidly at 1-month post-denosumab administration (both in the initial 12- month [Q3M, Q6M groups] and long-term treatment [P/Q3M, P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. Conclusion Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on ES progression, higher dosing frequency at an earlier treatment stage may be needed to optimise treatment. Denosumab was generally well tolerated.

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Impact of age on the efficacy and safety of peficitinib (ASP015K) for the treatment of rheumatoid arthritis

Modern Rheumatology ◽

10.1093/mr/roab058 ◽

2021 ◽

Author(s):

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Daisuke Kato ◽

Yuichiro Kaneko ◽

Musashi Fukuda ◽

...

Keyword(s):

Herpes Zoster ◽

Filtration Rate ◽

Estimated Glomerular Filtration Rate ◽

Incidence Rates ◽

Phase 2 ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Related Disease ◽

Serious Infections

ABSTRACT Objectives To evaluate peficitinib efficacy and safety in Asian patients with rheumatoid arthritis (RA), stratified by age (≥20–<50, ≥50–<65, and ≥65 years). Methods Efficacy data from two Phase 3 studies were analysed. Safety data from one Phase 2, two Phase 3, and one open-label extension study were pooled. Incidence rates per 100 patient-years of adverse events of special interest were calculated, and Cox proportional hazard analysis was conducted. Results 1052 patients received peficitinib for 2 years (median). Peficitinib demonstrated efficacy improvements versus placebo across all age categories. Incidence rates (95% confidence interval) per 100 patient-years for ≥20–<50, ≥50–<65, and ≥65 years were 0.8 (0.4, 1.9), 2.6 (1.8, 3.7), and 4.7 (3.1, 7.0) for serious infections and 3.7 (2.5, 5.4), 6.4 (5.0, 8.2), and 11.2 (8.5, 14.7) for herpes zoster–related disease, respectively. Twenty patients reported malignancies in pooled Phase 2/3 studies. Incidences of serious infections and herpes zoster–related disease increased significantly with age, but there was no association with baseline estimated glomerular filtration rate. Conclusions Peficitinib was efficacious in adult Asian RA patients of all ages. Age, but not estimated glomerular filtration rate, was associated with serious infections and herpes zoster–related disease, demonstrating the importance of an appropriate RA treatment strategy in older patients.

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Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNFαBlockers in Rheumatoid Arthritis and Spondyloarthritis Patients

BioMed Research International ◽

10.1155/2015/604872 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Inesa Arstikyte ◽

Giedre Kapleryte ◽

Irena Butrimiene ◽

Algirdas Venalis

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Events ◽

Clinical Characteristics ◽

Term Treatment ◽

High Serum ◽

Treatment Discontinuation ◽

Increased Risk ◽

Long Term Treatment ◽

Biologic Drug

Objective. To analyze the clinical relevance of the levels of TNFαblockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time.Methods. Clinical characteristics (disease activity, and adverse events), serum TNFαblockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFαblockers for a median of 28 months.Results. Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and nonresponders(P>0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08–120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64–52.52)).Conclusion. Patients not responding to treatment had higher serum anti-ADA and anti-INF Ab concentrations. Anti-INF Ab formation is related to increased risk of infusion related reactions, changing to another biologic drug, and treatment discontinuation.

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Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-220822 ◽

2021 ◽

Vol 81 (2) ◽

pp. 206-213

Author(s):

Kevin L Winthrop ◽

Peter Nash ◽

Kunihiro Yamaoka ◽

Eduardo Mysler ◽

Nasser Khan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Herpes Zoster ◽

Cox Regression ◽

Janus Kinase ◽

Phase Iii ◽

Cox Regression Analysis ◽

Increased Risk ◽

History Of ◽

Event Rates

BackgroundUpadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis (RA). JAK inhibitors have been associated with an increased risk of herpes zoster (HZ) in patients with RA.ObjectivesTo evaluate the incidence and risk factors for HZ in UPA-treated patients with RA from the UPA phase III clinical trial programme.MethodsExposure-adjusted incidence/event rates for HZ were determined in patients receiving UPA (monotherapy or combination therapy) in six randomised phase III trials (data cut-off on 30 June 2020). HZ incidence and event rates were also determined in patients receiving methotrexate (MTX) monotherapy or adalimumab (ADA) + MTX. Multivariable Cox regression analysis was used to identify HZ risk factors in UPA-treated patients.ResultsA total of 5306 patients were included in this analysis. The incidence rate of HZ/100 patient-years (95% CI) was 0.8 (0.3 to 1.9), 1.1 (0.5 to 1.9), 3.0 (2.6 to 3.5) and 5.3 (4.5 to 6.2), in the MTX monotherapy, ADA + MTX, UPA 15 mg and UPA 30 mg groups, respectively. The majority of HZ cases with UPA (71%) involved a single dermatome. Prior history of HZ and Asian region were HZ risk factors in UPA-treated patients.ConclusionIn the UPA phase III RA clinical programme, HZ incidence and event rates were higher with UPA versus ADA + MTX or MTX monotherapy, and higher with the 30 mg versus 15 mg dose. Patients from Asia and those with a history of HZ may be at increased risk of HZ while receiving UPA.

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FRI0141 CHARACTERIZATION OF SERIOUS INFECTIONS WITH UPADACITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2761 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 654-655

Author(s):

K. Winthrop ◽

L. Calabrese ◽

F. Van den Bosch ◽

K. Yamaoka ◽

C. Selmi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Cox Regression ◽

Opportunistic Infections ◽

Oral Candidiasis ◽

Univariate Analysis ◽

Janus Kinase ◽

Research Support ◽

Phase 3 ◽

Increased Risk

Background:Upadacitinib (UPA) is a selective and reversible Janus kinase (JAK) inhibitor with an approved dose of 15 mg once daily (QD) for the treatment of rheumatoid arthritis (RA). Patients (pts) receiving JAK inhibitors have been reported to be at increased risk of developing serious infection events (SIE) and opportunistic infections (OI).Objectives:To evaluate the incidence of SIEs and OIs in pts with RA receiving UPA and active comparators in the Phase 3 SELECT clinical trial program.Methods:The exposure-adjusted event rate (EAER) per 100 patient-years (E/100 PY) of SIEs and OIs was determined in pts receiving UPA in five randomized Phase 3 trials (SELECT-EARLY, SELECT-MONOTHERAPY, SELECT-NEXT, SELECT-COMPARE, and SELECT-BEYOND), of which four evaluated both UPA 15 mg and 30 mg QD doses and one (SELECT-COMPARE) evaluated only UPA 15 mg QD. Incidences of SIEs and OIs were also determined in pts receiving adalimumab (ADA) + methotrexate (MTX) in SELECT-COMPARE and MTX monotherapy in SELECT-EARLY. Data were analyzed descriptively, with no statistical comparisons between groups or doses. Risk factors for SIEs were determined using a univariate Cox regression model. The data cut-off was June 30, 2019.Results:Overall, 2629 pts who received UPA 15 mg, 1204 pts who received UPA 30 mg, 579 pts who received ADA + MTX, and 314 pts who received MTX monotherapy were included in this analysis. The EAERs (E/100 PYs [95% CI]) of SIEs were 3.2 (2.7–3.7) in the UPA 15 mg group, 5.7 (4.8–6.8) in the UPA 30 mg group, 3.9 (2.6–5.6) in pts receiving ADA + MTX, and 3.1 (1.7–5.2) in pts receiving MTX monotherapy. Pneumonia was the most common SIE, with EAERs (E/100 PYs [95% CI]) of 0.7 (0.5–1.0), 1.3 (0.9–1.9), 0.7 (0.2–1.5), and 0.7 (0.1–1.9) in the UPA 15 mg, UPA 30 mg, ADA + MTX, and MTX monotherapy groups, respectively. Rates of OIs (including oral candidiasis and disseminated herpes zoster [HZ]) (E/100 PYs [95% CI]) were 0.7 (0.5–1.0), 1.3 (0.9–1.9), 0.4 (0.1–1.1), and 0 (0–0) in the UPA 15 mg, UPA 30 mg, ADA + MTX, and MTX monotherapy groups, respectively. Oral candidiasis was the most frequent OI with EAERs (E/100 PYs [95% CI]) of 0.4 (0.2–0.6) in the UPA 15 mg group, 0.6 (0.3–1.0) in the UPA 30 mg group, 0.4 (0.1–1.1) in the ADA + MTX group, and 0 (0–0) in the MTX monotherapy group. Serious adverse events of HZ were only reported in the UPA groups (0.2 E/100 PYs [95% CI: 0.1–0.3] and 0.6 E/100 PYs [95% CI: 0.4–1.1] in the UPA 15 mg and 30 mg groups, respectively). Overall, there were 3 (4 coded events), 3, 1, and 0 pts who had active tuberculosis events in the UPA 15 mg, UPA 30 mg, ADA + MTX, and MTX monotherapy groups, respectively. Risk factors for SIEs are shown in the Figure. For both UPA doses, age ≥75 years and smoking were noted to have hazard ratios >1.Conclusion:The incidence rate of SIEs and OIs was higher in the UPA 30 mg group than the UPA 15 mg group. SIEs observed with UPA 15 mg were similar to that seen with ADA although the rates of HZ were higher on UPA. Pts with RA who are ≥75 years old and/or smokers may be at higher risk than other pts with RA for SIEs while receiving UPA.Figure.Univariate analysis of SIE risk factorsDisclosure of Interests:Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Leonard Calabrese Consultant of: AbbVie, GSK, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Sanofi, Horizon, Crescendo, and Gilead, Speakers bureau: Sanofi, Horizon, Crescendo, Novartis, Genentech, Janssen, and AbbVie, Filip van den Bosch Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Kunihiro Yamaoka Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Mitsubishi-Tanabe Pharma Corporation, Pfizer Japan Inc., and Takeda Pharmaceutical Company Ltd, Carlo Selmi Grant/research support from: AbbVie, Janssen, MSD, Novartis, Pfizer, Celgene, and Leo Pharma, Consultant of: Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and Sanofi-Regeneron, Speakers bureau: AbbVie, Aesku, Alfa-Wassermann, Bristol-Myers Squibb, Biogen, Celgene, Eli-Lilly, Grifols, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB Pharma, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Barbara Hendrickson Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ivan Lagunes-Galindo Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB

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MO035HISTORICAL CONTROL ANALYSIS DEMONSTRATES SUPERIOR REDUCTION OF PLASMA GLOBOTRIAOSYLCERAMIDE BY VENGLUSTAT COMPARED WITH PLACEBO OR AGALSIDASE BETA IN CLASSIC FABRY DISEASE PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo035 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Dominique P Germain ◽

William Wilcox ◽

Patrick Deegan ◽

Kejian Liu ◽

Eric Hailman ◽

...

Keyword(s):

Fabry Disease ◽

Term Treatment ◽

Historical Control ◽

Agalsidase Beta ◽

Phase 2 ◽

Phase 3 ◽

Glucosylceramide Synthase ◽

Phase 2 Study ◽

Long Term Treatment

Abstract Background and Aims Fabry disease (FD) is a rare, X-linked, genetic disorder caused by pathogenic variants in the gene for the lysosomal enzyme alpha-galactosidase A (αGal-A). The progressive accumulation of glycosphingolipids, most notably globotriaosylceramide (GL-3), leads to renal, cardiovascular, and other clinical manifestations over decades. In a single-arm phase 2 study, glucosylceramide synthase inhibition with venglustat led to a reduction in lysosomal GL-3 inclusions in skin capillary endothelial cells, as well as a progressive reduction in plasma GL-3 to normal levels by 26 weeks, with a continued decrease to low-normal levels after 3 years of therapy. We used patient data from a previously completed placebo-controlled phase 3 study of agalsidase beta (Fabrazyme) as historical control to compare the effect of venglustat treatment with placebo over 6 months and with agalsidase beta over 3 years. Methods In the venglustat phase 2 study, previously untreated classic FD patients were treated with daily venglustat for up to 3 years (NCT02228460, NCT02489344). For comparison to placebo, change in plasma GL-3 levels after 26 weeks of venglustat treatment was compared with matched historical control data from previously untreated classic FD patients who were treated for 20 weeks with placebo in the phase 3 agalsidase beta study (Eng et al, N Engl J Med 345:9, 2001). For comparison to agalsidase beta, the historical control arm was matched patients treated with agalsidase beta in the phase 3 study; change in plasma GL-3 was compared at multiple time points up to 3 years. Entry criteria and baseline characteristics were similar between the two studies. Due to the much larger numbers of patients in the phase 3 agalsidase beta study, venglustat patients were matched 1:X (variable match) with control (placebo or agalsidase beta) patients based on propensity scores using baseline variables of age, plasma GL-3, gender, UPCR (< 500 vs 500-1000 vs >1000 mg/g), and eGFR (<80 vs >= 80 mL/min/1.73m2) as matching variables. Plasma GL-3 was measured at Sanofi Genzyme by LC/MS/MS, using the same method for the two studies, with controls in place to assure assay consistency. Results Venglustat patients (N=11) were matched to 19 patients for the placebo comparison and to 28 patients for comparison to Fabrazyme. All patients in all 3 groups were male and had elevated plasma GL-3, UPCR <500 mg/g, and eGFR ≥80 mL/min/1.73m2 at baseline. Mean ages in the 3 groups were 26.6, 25.7, and 26.5 years after matching, respectively. Venglustat treatment for ∼6 months led to a highly significant reduction in plasma GL-3 compared to placebo of 3.62 vs 1.06 µg/mL (p <0.0001). Long-term treatment with venglustat yielded similar reductions in plasma GL-3 compared to agalsidase beta for the first year of treatment, but while GL-3 levels reached a plateau with agalsidase beta, the reduction with venglustat continued with longer treatment and was significantly greater than that of agalsidase beta after 2 years (p=0.0351) or 3 years (p=0.0081) (Figure). Plasma GL-3 levels after 3 years of treatment were 1.90 and 4.44 µg/mL for venglustat and agalsidase beta, respectively (normal range ≤7.02 µg/mL). Conclusions Glucosylceramide synthase inhibition with venglustat led to a significantly greater reduction in plasma GL-3 compared to placebo after 6 months, and treatment for 2-3 years led to a significantly greater reduction in plasma GL-3 compared with agalsidase beta. These results highlight the potential of long-term treatment venglustat to reverse the accumulation of GL-3 in classic FD.

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Integrated safety analysis of filgotinib in patients with moderately to severely active rheumatoid arthritis receiving treatment over a median of 1.6 years

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-221051 ◽

2021 ◽

pp. annrheumdis-2021-221051

Author(s):

Kevin L Winthrop ◽

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Alan Kivitz ◽

Franziska Matzkies ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Active Rheumatoid Arthritis ◽

Incidence Rates ◽

Janus Kinase ◽

Major Adverse Cardiovascular Events ◽

Link Type ◽

Serious Infection ◽

Grade 3 ◽

Adjusted Incidence

ObjectiveTo characterise safety of the Janus kinase-1 preferential inhibitor filgotinib in patients with moderately to severely active rheumatoid arthritis.MethodsData were integrated from seven trials (NCT01668641, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700, NCT03025308). Results are from placebo (PBO)-controlled (through week (W)12) and long-term, as-treated (all available data for patients receiving ≥1 dose filgotinib 200 (FIL200) or 100 mg (FIL100) daily) datasets. We calculated exposure-adjusted incidence rates (EAIRs)/100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs).Results3691 patients received filgotinib for 6080.7 PYE (median 1.6, maximum 5.6 years). During the PBO-controlled period, TEAEs, including those of grade ≥3, occurred at comparable rates with filgotinib or PBO; long-term EAIRs of TEAEs grade ≥3 were 6.4 and 7.6/100PYE for FIL200 and FIL100. EAIRs for deaths were 0.6/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.5 and 0.3/100PYE for FIL200 and FIL100. EAIRs for serious infection were 3.9, 3.3 and 2.4/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.6 and 3.1/100PYE for FIL200 and FIL100. EAIRs for herpes zoster were 0.6, 1.1, and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.8 and 1.1/100PYE for FIL200 and FIL100. EAIRs for major adverse cardiovascular events were 0, 1.7 and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.4 and 0.6/100PYE for FIL200 and FIL100. No venous thromboembolism occurred during the PBO-controlled period; long-term EAIRs were 0.2 and 0/100PYE for FIL200 and FIL100.ConclusionsOver a median of 1.6 and maximum of 5.6 years of exposure, safety/tolerability of FIL200 and FIL100 were similar, with a lower incidence of infections with FIL200 among the long-term, as-treated dataset.

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