THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects

Voss, Jeffrey W.; Graff, Candace; Schwartz, Arthur G.; Hyland, Deborah; Argiriadi, M.A.; Camp, Heidi S.; Dowding, L.; Friedman, Michael; Frank, Karen M.; George, Jonathan S.; Goedken, Eric R.; Schiavo, Gessica; Morytko, Michael; O’Brien, Rebecca L.; Padley, Robert J.; Rozema, Michael J.; Rosebraugh, Matthew; Stewart, Kent D.; Wallace, Grier A.; Wishart, Neil; Murtaza, Anwar; Olson, L.

doi:10.1136/annrheumdis-2014-eular.3823

Cited by 30 publications

(22 citation statements)

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“…19 Upadacitinib selectively inhibits JAK1 and is less potent against the other isoforms, JAK2, JAK3, and tyrosine kinase 2. 20 The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit-risk profile compared to less selective JAK inhibitors. [21][22][23][24] Upadacitinib pharmacokinetics were evaluated in Phase 1 studies following single doses of 1 to 48 mg and multiple doses of 3 to 24 mg twice-daily (BID) using the immediate-release (IR) capsule formulation.…”

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confidence: 99%

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials

Nader

Stodtmann

Friedel

et al. 2019

The Journal of Clinical Pharma

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Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2‐compartment model with first‐order absorption and lag time for the immediate‐release formulation and mixed zero‐ and first‐order absorption with lag time for the extended‐release formulation, and linear elimination adequately described upadacitinib plasma concentration–time profiles. The oral bioavailability of upadacitinib extended‐release formulation was estimated to be approximately 80% relative to the immediate‐release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady‐state area under the plasma concentration–time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady‐state AUC, while subjects with rheumatoid arthritis had 35% higher steady‐state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady‐state exposures.

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confidence: 99%

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials

Nader

Stodtmann

Friedel

et al. 2019

The Journal of Clinical Pharma

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“…ABT‐494 is currently in development to treat active RA in adult patients. ABT‐494 is a JAK inhibitor with enhanced selectivity for JAK‐1 compared with JAK‐2 (∼74‐fold higher, with a 50% inhibition concentration [IC 50 ] of 8 n M compared with 600 n M , respectively) in cellular assays, and with enhanced selectivity for JAK‐1 compared with JAK‐3 (∼58‐fold higher, with an IC 50 of 40 n M compared with 2.3 µ M , respectively) in biochemical assays . This increased selectivity potentially offers an improved benefit–risk profile in patients with RA.…”

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Efficacy and Safety of ABT‐494, a Selective JAK‐1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Genovese

Smolen

Weinblatt

et al. 2016

Arthritis & Rheumatology

180

149

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ObjectiveTo evaluate the efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).MethodsThree hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.ResultsAt week 12, the proportion of ACR20 responses was higher with ABT‐494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose‐response relationship among all ABT‐494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT‐494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28‐CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community‐acquired pneumonia) occurred with ABT‐494 at 12 mg. There were dose‐dependent increases in high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.ConclusionThis study evaluated a broad range of doses of ABT‐494 in RA patients with an inadequate response to MTX. ABT‐494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.

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“…Interleukin‐6 (IL‐6) and the interferons (IFNs) are known to signal primarily through JAK‐1, and based on the proven action of tocilizumab in RA, which functions via IL‐6 inhibition, JAK‐1 is thought to play an important role in RA disease pathophysiology. In biochemical assays, ABT‐494 is ∼74‐fold more selective for JAK‐1 than for JAK‐2 (which is involved in erythropoiesis) and ∼58‐fold more selective for JAK‐1 than for JAK‐3 (which is involved in immunosurveillance) . The enhanced selectivity of ABT‐494 for JAK‐1 over JAK‐2 and JAK‐3 (13) may offer an improved benefit–risk profile in patients with RA.…”

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A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

Kremer

Emery

Camp

et al. 2016

Arthritis & Rheumatology

156

128

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ObjectiveTo compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.MethodsIn this 12‐week, double‐blind, placebo‐controlled, dose‐ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti‐TNF agent were randomized equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12.ResultsAt week 12, significantly more patients receiving ABT‐494 (53–71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose‐response relationship among all ABT‐494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT‐494 (36–42% and 22–26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) were significantly greater for all doses of ABT‐494 than for placebo (P ≤ 0.01). Onset of action of ABT‐494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28‐CRP (P < 0.001 for 6–18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT‐494, but no infections were serious. No deaths were reported among those receiving ABT‐494.ConclusionIn patients with an inadequate response or intolerance to anti‐TNF agents, ABT‐494 added to MTX showed rapid, dose‐dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.

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THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects

Cited by 30 publications

References 0 publications

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials

Efficacy and Safety of ABT‐494, a Selective JAK‐1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

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