Data Promising, Inconclusive on JAK Inhibitors for Crohn’s Disease

Tommaso Lorenzo Parigi, MD

Untangling clinical data for Janus kinase (JAK) inhibitors for the treatment of Crohn’s disease has been challenging.

A team of investigators, including Tommaso Lorenzo Parigi, MD, Department of Biomedical Sciences, Humanitas University, Virginia Solitano, MD, Department of Biomedical Sciences, Humanitas University, Laurent Peyrin-Biroulet, MD, PhD, Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, and Silvio Danese, MD, PhD, Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, recently examined the clinical data of 3 key and promising JAK inhibitors in this patient population.

The Disease

Often times treatments that work for Crohn’s disease, also work for ulcerative colitis, and vice versa. This is particularly highlighted by single proinflammatory cytokine treatments. However, there remains a significant percentage of patients who will still not respond to this treatment class.

To counteract this, drug developers have focused more on small molecule agents than monoclonal antibodies in recent years. Small molecules can cross the sphingolipid cell membrane and exert an effect inside of the cell.

“Their molecular characteristics and size allow a more convenient oral administration and avoid the development of antidrug antibodies,” the authors wrote.

JAK Inhibitors

The most promising families of small molecules for the treatment of IBD is likely JAK inhibitors, a group of intracellular tyrosine kinases that bind different cytokine receptors. This leads to phosphorylation of signal transducer and activation of transcription (STAT) molecules that can regulate the transcription of targeted genes.

There are 4 isoforms of JAK with distinct tissue expression and mediating the signaling of different cytokines with various effects that are both pro- and anti-inflammatory.

An example of this is with erythropoietin, a granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) that binds to membrane receptors that depend on JAK signaling.

The investigators said STAT1 and STAT2 mediate type 1 interferon signal maintaining barrier integrity, while STAT3 and STAT6 directly promote the proliferation and migration of epithelial cells in response to harmful external factors. This shows inhibiting 1 or more JAK isoforms can be intricate and difficult to predict.

Other JAK inhibitors that have been success treating ulcerative colitis but less successful for Crohn’s disease include tofacitinib, upadacitinib, and filgotinib.

Tofacitinib

Tofacitinib, which was approved for the treatment of ulcerative colitis by the US Food and Drug Administration (FDA) in 2019, in particularly has been targeted as a Crohn’s disease treatment.

While there have been some signs this treatment can be effective, ultimately there was no difference found in clinical remission or clinical response in comparison to placebo.

“With regards to tofacitinib, despite the design of both trials has been criticized and the high placebo response penalized treatment arms, it is unlikely that a real efficacy would have gone undetected twice,” the authors wrote.

Filgotinib

Much like tofacitinib, filgotinib has also shown promise, albeit inconclusive promise, in treating Crohn’s disease. Following positive phase 2 results where 47% of the patient population reached clinical remission at week 10 compared to 23% for the placebo group, there is currently a phase 3 trial underway.

However, in the phase 2 trial, the investigators found secondary endpoints of endoscopic response, endoscopic remission, mucosal healing, and deep remission did not reach statistical significance for benefit.

Upadacitinib

Finally, upadacitinib has also been similarly tested and shown promise. In fact, the difference in these trials is 96% of patients in the CELEST phase 2 trials were previously exposed to anti-TNF therapy.

In this trial, investigators found no dosage of the drug was superior to placebo for the induction of clinical remission, with no clear dose response observed.

However, endoscopic remission was met by most dosages and the maintenance treatment continued clinical and endoscopic responses, as well as the reduction of inflammatory markers in patients who responded during induction.

Safety

There are some safety concerns regarding this class of treatments, but some of the data for patients with IBD was deemed “reassuring.”

However, there has been concerns in other disease states.

The rate of thrombotic events in patients treated with upadacitinib, JAK1-selective, suggests that thrombosis could be more a class, rather than JAK2, related effect and there have been FDA warnings for cardiovascular and cancer risks in this class of drugs.

Filgotinib has also had a history of toxicity and reduced sperm counts for patients with rheumatoid arthritis.

However, it is most of the data regarding this class of treatment for Crohn’s disease is promising.

“In conclusion, the failure of tofacitinib trials should not overshadow the overall positive data of filgotinib and upadacitinib,” the authors wrote “The phase 3 studies of these agents are eagerly awaited, and so are the upcoming phase 2 trials of TYK2 inhibitors. Thus far, a future for JAK inhibitors in CD remains realistic.”

The editorial, “Do JAK inhibitors have a realistic future in treating Crohn’s disease?,” was published online in Expert Review of Clinical Immunology.