Upadacitinib

Clinical data
Synonyms	ABT-494
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic (CYP3A major, CYP2D6 minor) [1]
Elimination half-life	6-15 hours[1]
Identifiers
IUPAC name (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
CAS Number	1310726-60-3 Y
PubChem CID	58557659
IUPHAR/BPS	9246
ChemSpider	44210449 Y
UNII	4RA0KN46E0
ChEMBL	CHEMBL3622821 Y
Chemical and physical data
Formula	C17H19F3N6O
Molar mass	380.38 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCC1CN(CC1C2=CN=C3N2C4=C(NC=C4)N=C3)C(=O)NCC(F)(F)F
InChI InChI=1S/C17H19F3N6O/c1-2-10-7-25(16(27)24-9-17(18,19)20)8-11(10)13-5-22-14-6-23-15-12(26(13)14)3-4-21-15/h3-6,10-11,21H,2,7-9H2,1H3,(H,24,27)/t10-,11+/m1/s1 Y Key:WYQFJHHDOKWSHR-MNOVXSKESA-N Y

Upadacitinib (code name ABT-494) is a drug which is currently under investigation for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and psoriatic arthritis. It was developed by the biotech company AbbVie.

Mechanism of action[edit]

The Janus kinases (JAKs) 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 (jakinibs) 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.^[2][3] Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 (74-fold), JAK3 (58-fold) and TYK2 subtypes.^[4]

Clinical trials[edit]

Phase I studies[edit]

A phase I study revealed that upadacitinib followed a bi-exponential disposition with a terminal half-life of 6–16 hours.^[1] 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 (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).^[5] Inhibition of CYP3A by ketoconazole increased total AUC, indicating the importance of this metabolic route.

Phase II studies[edit]

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[edit]

In the first study, 276 rheumatoid arthritis patients were recruited who had previously experienced inadequate response to anti–tumor necrosis factor (TNF) therapy and were currently on a stable dose of methotrexate.^[6] 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 (ACR20). 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 (36–42% and 22– 26%, respectively). Adverse events included headache, nausea, and infection but no infections were serious.

BALANCE II[edit]

In the second phase IIb study, 300 rheumatoid arthritis patients were recruited who have had an inadequate response to methotrexate.^[7] 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 (ACR20). 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. (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%). 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[edit]

^{[needs update]}
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.^[8][9] 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 (soft stool frequency or daily abdominal pain score) at week 16 and endoscopic remission at week 12 or 16. Secondary endpoints included significant clinical response (≥30% reduction in symptoms) at week 16 and endoscopic response (≥25% decrease in symptoms) 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[edit]

Abbvie has planned a total of six phase III trials that will evaluate over 4,000 patients with moderate to severe rheumatoid arthritis.^[10] Two phase III trials are planned studying patients with psoriatic arthritis and one in patients with ulcerative colitis.

See also[edit]

Filgotinib is also a selective inhibitor of JAK1.

References[edit]