Upadacitinib
Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis in adults where methotrexate did not work well or could not be tolerated. It was approved for medical use in the United States and in the European Union in 2019, and was developed by the biotech company AbbVie.
Common side effects include upper respiratory tract infections, nausea, cough, and fever.
Upadacitinib works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.
Medical uses
Upadacitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Upadacitinib may be used as monotherapy or in combination with methotrexate.Contraindications
The drug is contraindicated in people with active tuberculosis and other severe infections, severe liver impairment, and during pregnancy.The use of upadacitinib in combination with other Janus kinase inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and ciclosporin is not recommended.
Interactions
Substances that strongly inhibit the liver enzyme CYP3A4, such as ketoconazole, itraconazole or clarithromycin, increase upadacitinib concentrations in the body. In a study, ketoconazole increased its AUC by 75%. Conversely, substances that strongly induce CYP3A4 lower upadacitinib concentrations. For example, rifampicin reduced the AUC by 60% in a study.Upadacitinib seems to be a weak inducer of CYP3A4, as it lowers concentrations of other substrates of this enzyme. It has no effect on substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6.
Side effects
Common side effects are upper respiratory tract infections such as common cold and sinus infections, nausea, cough, fever, and increased liver enzymes. Serious side effects include infections, including life-threatening ones, such as pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections.Pharmacology
Mechanism of action
The Janus kinases are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. There are four JAK subtypes, each of which has overlapping receptor responsibilities. Inhibitors of this enzyme family have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn's disease. However, the first generation of these drugs, tofacitinib and ruxolitinib, lacked subtype selectivity, affecting JAK1/JAK3 and JAK1/JAK2 respectively. This has led to dose-limiting side effects in this otherwise promising class of drugs. Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2, JAK3 and tyrosine kinase 2 subtypes.Pharmacokinetics
After oral intake, upadacitinib reaches highest concentrations in the blood plasma after two to four hours. A fatty meal has no clinically relevant effect on its resorption. Steady-state conditions are reached after four days; accumulation is minimal. There is no significant first pass effect. When in the bloodstream, 52% of the substance are bound to plasma proteins. It is mainly metabolized by CYP3A4, and possibly to a minor extent by CYP2D6. The most important pathway consists of oxidation to a carboxylic acid and subsequent glucuronidation, yielding a metabolite called M4. However, 79% of the drug are circulating in form of upadacitinib itself, and only 13% as M4. Other metabolites are only present in small fractions. None are pharmacologically active.The drug is excreted mainly as the original substance, of which 38% are found in the feces and 24% in the urine. The mean terminal half-life is 9 to 14 hours.
Clinical trials
Phase I studies
A phase I study revealed that upadacitinib followed a bi-exponential disposition with a terminal half-life of 6–16 hours. There was no significant accumulation over the dose range of 3–36 mg per day. No interaction was found in rheumatoid arthritis patients taking methotrexate. The most common adverse event was headache but its incidence was similar to that when taking placebo. An investigation into absorption and metabolism found that dosing after a high-fat meal had no effect on upadacitinib total drug exposure over time. Inhibition of CYP3A by ketoconazole increased total AUC, indicating the importance of this metabolic route.Phase II studies
Two phase IIb studies were initiated to study the efficacy and safety of upadacitinib in patients with rheumatoid arthritis and one phase II study was initiated in patients with Crohn's disease.BALANCE I
In the first study, 276 rheumatoid arthritis patients were recruited who had previously experienced inadequate response to anti–tumor necrosis factor therapy and were currently on a stable dose of methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria. At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone. Adverse events included headache, nausea, and infection but no infections were serious.BALANCE II
In the second phase IIb study, 300 rheumatoid arthritis patients were recruited who have had an inadequate response to methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria. At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone. than with placebo. Improvement in symptoms was rapid, with significant changes in disease scores by week 2. Adverse events were mild with infection being the most serious. One case of community-acquired pneumonia occurred at 12 mg.CELEST
In this 16-week study, 220 patients were recruited with moderately to severely active Crohn's disease. Participants must have also experienced an inadequate response to or intolerance to Immunotherapy or TNF inhibitors. Patients were randomized to therapy with upadacitinib at 3, 6, 12, 24 mg twice daily or 24 mg once daily for 16 weeks or placebo, followed by blinded extension therapy for 36 weeks. The co-primary endpoints were the proportion of patients who achieved clinical remission at week 16 and endoscopic remission at week 12 or 16. Secondary endpoints included significant clinical response at week 16 and endoscopic response at week 12 or 16. At 16 weeks 22% of patients taking the 24 mg twice daily dose achieved endoscopic remission with upadacitinib compared to 0% of patients taking placebo. 27% of patients taking the 6 mg twice daily dose achieved clinical remission compared to 11% of patients taking placebo. Adverse events did not appear to be dose-related. A single case of non-melanoma skin cancer was reported in the 24 mg twice daily group.Phase III studies
Abbvie has planned a total of six phase III trials that will evaluate over 4,000 patients with moderate to severe rheumatoid arthritis. Two Phase III trials are planned studying participants with psoriatic arthritis and one in participants with ulcerative colitis.SELECT-COMPARE
In SELECT-COMPARE 1629 patients with moderate to severe rheumatoid arthritis and inadequate response to methotrexate were randomized to once-daily upadacitinib 15mg, placebo, or adalimumab 40mg, on stable background methotrexate. Primary endpoints were ACR20 and DAS28CRP<2.6 versus placebo at week 12; inhibition of radiographic progression was evaluated at week 26. The study was designed and powered to test for non-inferiority and superiority of upadacitinib versus adalimumab clinically and functionally. At week 12, both primary endpoints were met for upadacitinib versus placebo. ACR20 was achieved by 71% versus 36%, and DAS28CRP<2.6 by 29% versus 6%. Upadacitinib was superior to adalimumab for ACR50, DAS28CRP≤3.2, ΔPain and ΔHAQDI. At week 26, more patients on upadacitinib vs placebo or adalimumab achieved low disease activity or remission. Radiographic progression was less and observed in fewer patients receiving upadacitinib versus placebo. Up to week 26, adverse events including serious infections were comparable for upadacitinib and adalimumab. The proportions of patients with serious AEs and AEs leading to discontinuation were highest for adalimumab; the proportion with herpes zoster and CPK elevations was highest for upadacitinib. Three malignancies, five MACE, and four deaths were reported, none on upadacitinib. Six venous thromboembolic events were reported .Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms and physical function in RA patients on background methotrexate, and significantly inhibited radiographic progression versus placebo, while the overall safety profile was generally similar to adalimumab, except for higher rates of herpes zoster and CPK elevations on upadacitinib.
History
Upadacitinib was approved for medical use in the United States in August 2019.The U.S. Food and Drug Administration approved upadacitinib based on evidence from five clinical trials of 3,141 subjects with active rheumatoid arthritis. The trials were conducted in Australia, New Zealand, Israel, South Africa, Asia, North/Central/South America, and Europe.
Five trials established the benefits and side effects of upadacitinib. Trials enrolled subjects with moderate to severe active RA in whom disease-modifying antirheumatic drugs did not work well or could not be tolerated. All subjects had at least six tender and six swollen joints, and increased levels of high sensitivity C-reactive protein. hsCRP is a substance produced by the body to protect itself from illness. Trials lasted up to 5 years.
Trial 1 enrolled subjects who had never been treated with MTX. Subjects were randomly assigned to receive one of two doses of upadacitinib or MTX daily for 24 weeks. Neither the subject nor the healthcare providers knew which medication was being given until after this 24-week treatment period.
Trial 2 enrolled subjects in whom MTX did not work well. Subjects were randomly assigned to receive one of two doses of upadacitinib daily by mouth or continue their usual dose of MTX for 14 weeks. At week 14, subjects who were assigned to MTX received upadacitinib by mouth daily. Neither the subject nor the healthcare providers knew which medication was being given.
Trial 3 enrolled subjects in whom DMARDS did not work well. Subjects were randomly assigned to receive one of two doses of upadacitinib or placebo daily by mouth in addition to DMARDS for 12 weeks. At week 12, subjects who received placebo were re-assigned to upadacitinib daily. Neither the subject nor the healthcare providers knew which medication was being given.
Trial 4 enrolled subjects in whom MTX did not work well. Subjects were randomly assigned to receive upadacitinib or placebo daily by mouth in addition to MTX for 14 weeks. Subjects receiving placebo who did not have adequate improvement of signs and/or symptoms could be switched to upadacitinib after week 14. At week 26, all subjects receiving placebo were switched to upadacitinib once daily by mouth. Neither the subject nor the healthcare providers knew which medication was being given.
Trial 5 enrolled subjects in whom DMARDS did not work well or could not be tolerated. Subjects were randomly assigned to receive one of two doses of upadacitinib or placebo treatment daily added to DMARDs for 12 weeks. At week 12, subjects who received placebo were re-assigned to upadacitinib daily.
The benefit of upadacitinib was measured by comparing the proportion of subjects treated with upadacitinib who achieved an American College of Rheumatology 20 response at week 12 or week 14 to the proportion of subjects treated with MTX or placebo who achieved an ACR20 response. ACR20 is a 20% improvement in signs and symptoms of RA.
Upadacitinib was approved for medical use in the European Union in December 2019.