History
Upadacitinib was approved for medical use in the United States in August 2019.[30][10]
The US Food and Drug Administration (FDA) approved upadacitinib based on evidence from five clinical trials (Trial 1/NCT02706873, Trial 2/NCT02706951, Trial 3/NCT02675426, Trial 4/NCT02629159, Trial 5/NCT02706847) of 3,141 participants with active rheumatoid arthritis (RA).[10] The trials were conducted in Australia, New Zealand, Israel, South Africa, Asia, North/Central/South America, and Europe.[10]
Five trials established the benefits and side effects of upadacitinib.[10] Trials enrolled participants with moderate to severe active RA in whom disease-modifying antirheumatic drugs did not work well or could not be tolerated.[10] All participants had at least six tender and six swollen joints, and increased levels of high sensitivity C-reactive protein (hsCRP).[10] hsCRP is a substance produced by the body to protect itself from illness.[10] Trials lasted up to 5 years.[10]
Trial 1 enrolled participants who had never been treated with methotrexate.[10] Participants were randomly assigned to receive one of two doses of upadacitinib or methotrexate daily for 24 weeks.[10] Neither the subject nor the healthcare providers knew which medication was being given until after this 24-week treatment period.[10]
Trial 2 enrolled participants in whom methotrexate did not work well.[10] Participants were randomly assigned to receive one of two doses of upadacitinib daily by mouth or continue their usual dose of methotrexate for 14 weeks.[10] At week 14, participants who were assigned to methotrexate received upadacitinib by mouth daily.[10] Neither the subject nor the healthcare providers knew which medication was being given.[10]
Trial 3 enrolled participants in whom disease-modifying antirheumatic drugs did not work well.[10] Participants were randomly assigned to receive one of two doses of upadacitinib or placebo daily by mouth in addition to disease-modifying antirheumatic drugs for 12 weeks.[10] At week 12, participants who received placebo were reassigned to upadacitinib daily.[10] Neither the subject nor the healthcare providers knew which medication was being given.[10]
Trial 4 enrolled participants in whom methotrexate did not work well.[10] Participants were randomly assigned to receive upadacitinib or placebo daily by mouth in addition to methotrexate for 14 weeks.[10] Participants receiving placebo who did not have adequate improvement of signs and/or symptoms could be switched to upadacitinib after week 14.[10] At week 26, all participants receiving placebo were switched to upadacitinib once daily by mouth.[10] Neither the subject nor the healthcare providers knew which medication was being given.[10]
Trial 5 enrolled participants in whom disease-modifying antirheumatic drugs did not work well or could not be tolerated.[10] Participants were randomly assigned to receive one of two doses of upadacitinib or placebo treatment daily added to disease-modifying antirheumatic drugs for 12 weeks.[10] At week 12, participants who received placebo were reassigned to upadacitinib daily.[10]
The benefit of upadacitinib was measured by comparing the proportion of participants treated with upadacitinib who achieved an American College of Rheumatology 20 (ACR20) response at week 12 or week 14 to the proportion of participants treated with MTX or placebo who achieved an ACR20 response.[10] ACR20 is a 20% improvement in signs and symptoms of RA.[10]
Upadacitinib was approved for medical use in the European Union in December 2019.[11]
In February 2023, upadacitinib was approved in the UK for treatment of Crohn's disease.[16][17]
In April 2023, upadacitinib was approved in the EU for the treatment of moderately to severely active Crohn's disease in adults.[18][19] The approval was for adults who "had an inadequate response, lost response, or were intolerant to conventional therapy or a biological agent".[31][32]
The efficacy and safety of upadacitinib were evaluated in two randomized induction trials of 857 participants with moderately to severely active Crohn's disease, CD-1 (NCT03345836) and CD-2 (NCT03345849).[21] Participants were randomized 2:1 to receive 45 mg of upadacitinib or placebo once a day for 12 weeks.[21] At week 12, a greater proportion of participants treated with 45 mg of upadacitinib, as compared to placebo, achieved clinical remission based on the Crohn's Disease Activity Index (CDAI), which measures clinical and laboratory variables that estimate disease activity in Crohn's disease.[21] Similarly, a greater proportion of participants treated with 45 mg of upadacitinib demonstrated improvement in intestinal inflammation as assessed by colonoscopy.[21]
To assess upadacitinib as a maintenance treatment, CD-3 (NCT03345823) evaluated 343 participants who responded to 12 weeks of 45 mg of upadacitinib once daily.[21] Participants were re-randomized to receive a maintenance regimen of 15 or 30 mg of upadacitinib once daily or placebo for 52 weeks, representing a total of at least 64 weeks of therapy.[21] At week 52, a greater proportion of participants treated with 15 mg or 30 mg of upadacitinib, as compared to placebo, achieved clinical remission based on the CDAI, and demonstrated improvement in intestinal inflammation as assessed by colonoscopy.[21]
Clinical trials
The safety and efficacy of upadacitinib were evaluated in multiple clinical trials:[13]
Phase I studies
A phase I study revealed that upadacitinib followed a bi-exponential disposition with a terminal half-life of 6–16 hours.[9] There was no significant accumulation over the dose range of 3–36 mg per day. No interaction was found in rheumatoid arthritis participants taking methotrexate. The most common adverse event was headache but its incidence was similar to that when taking placebo (15.6% for upadacitinib vs. 16.7% for 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 (area under the curve or AUC).[33]
