David Rubin, MD, on Efficacy and Safety of JAK Inhibitors for IBD

The advent of small molecule agents for inflammatory bowel disease (IBD), including Janus kinase (JAK) inhibitors, represents “what I believe is a paradigm shift in the management of IBD,” David T Rubin, MD, told the Advances in Inflammatory Bowel Disease (AIBD) regional meeting in his presentation on the efficacy and safety of JAK inhibitors.

Dr Rubin is the Joseph B Kirsner Professor In Medicine, chief of Gastroenterology, Hepatology and Nutrition, and director of the Digestive Diseases Center at the University of Chicago School of Medicine.

There are significant advantages to the use of JAK inhibitors, he said. “There are unmet needs in IBD; these therapies provided us with novel mechanisms of management and the convenience of an oral delivery system.” They also avoid specific challenges found with the use of monoclonal antibodies, such as immunogenicity and protein leakage among some patients, which Dr Rubin likened to “trying to fill a bathtub with the drain open.”

JAKs 1, 2, 3, and TYK 2 are enzymes that are related to activation of inflammation from cells; the system works through signal transduction and activation, Dr Rubin said. “If you block a Janus kinase enzyme you shut off a variety of different inflammatory pathways,” he explained. 

Two JAK inhibitors—tofacitinib, a pan-JAK agent, and upadacitinib, a selective JAK-1 inhibitor—are approved for use in the United States, while filgotinib is available in Europe.

Dr Rubin reviewed the pivotal OCTAVE 1 and OCTAVE 2 trials of tofacitinib for induction and maintenance in moderately to severely active UC, which led to the drug’s approval. At a dose of 10 mg BID, tofacitinib was superior to placebo in achieving the primary endpoint of clinical remission at week 8. The maintenance trial also showed tofacitinib’s superiority in maintaining clinical remission at week 52, with 41% of patients taking 10mg IBD and 34% on a dose of 5mg BID achieving the endpoint.

In a study of tofacitinib vs standard of care in acute severe UC, hospitalized patients who received 10 mg TID of tofacitinib were more likely to avoid colectomy at 90 days than those who received lower doses of the drug.

“I want to emphasize that while I do believe this makes sense, using the dose off-label has not yet been fully studied and I believe more work needs to be done before you routinely incorporate this for acute severe UC,” Dr Rubin cautioned.

The U-ACHIEVE trial of upadacitinib in patients who had an inadequate response to biologic therapies and U-ACCOMPLISH trial of biologic naïve patients demonstrated “quite substantial success” at week 8. In U-ACHIEVE patients achieved 64% clinical response rate by week 8. Results were even more impressive for the biologic naïve patients in U-ACCOMPLISH, Dr Rubin emphasized: “Look at the clinical response rate: 80% by week 8 at a dose of 45 mg.”

These results “suggest to us that patients who experienced previous biological failure don’t do quite as well as those who have not been exposed to a biologic, so maybe you want to use this drug earlier,” he continued. “Unfortunately, it’s labeled to be used after anti-TNF so it’s automatic that our patients will have been bio-exposed before they get this drug.”

The JAK inhibitors also work very fast to improve stool frequency, abdominal pain, rectal bleeding, and urgency, Dr Rubin said. “We’re talking days before the patient can tell it’s better. That’s really remarkable. I don’t even use corticosteroids if I know I can get a patient on this drug because it’s going to work so fast.”

Although tofacitinib did not succeed in its earlier trials for Crohn disease, upadacitinib does appear to be safe and effective for this indication. In a trial at the University of Chicago, Dr Rubin noted, “the drug worked better than even the clinical trials demonstrated.” Upadacitinib has also shown efficacy among patients who did not respond to tofacitinib, he added. “This is a therapy that we think will work quite well in Crohn’s and we’re excited to have it.”

Patients must respond inadequately or lose response to an anti-TNF prior to receiving JAK inhibitor therapy due to results of the ORAL Surveillance Study. This randomized, open-label, noninferiority safety endpoint study of tofacitinib vs anti-TNF was conducted among patients with active rheumatoid arthritis (RA) being treated with methotrexate, who were also over the age of 50 and had at least 1 cardiovascular risk factor. Patients were followed until they presented with an adverse event, Dr Rubin noted. This study showed an increase in the risk of deep vein thrombosis or venous thromboembolism.

As a result, the US Food and Drug Administration has required not only tofacitinib but all JAK inhibitors to be positioned after anti-TNF therapy has failed. Patients must be screened for risk of VTE and major adverse cardiovascular events; the agency also recommend that doses of JAK inhibitors be reduced after induction when possible.

However, Dr Rubin explained, that with tofacitinib and upadacitinib in UC, patients with refractory UC do better with higher doses of JAK inhibitors in maintenance —tofacitinib at 10 BID, upadacitinib at 30 QD. “Patients who’ve already been on biologics need higher doses for better outcomes, so this recommendation to reduce the dose is a bit of a paradox,” he said.

Open-label extension studies of tofacitinib have shown that the incidence of adverse events remained generally consistent among patients with moderate to severe UC compared to previous analyses. The only significant increased risk is for herpes zoster, “which is a known risk in this drug class that is dose- and time-related,” Dr Rubin explained. Vaccination with the attenuated vaccine is feasible even while the patient receives JAK inhibitor therapy, and the overall risk remains low.

In real-world practice, Dr Rubin said, JAK inhibitors should be used after a patient fails to respond adequately to an anti-TNF, and as monotherapy. Baseline labs, including a lipid panel, are important for monitoring potential side effects. Patients should also be screened for risk of VTE and vaccinated for herpes zoster.

He recommends dosing tofacitinib at 10 mg BID for 8 to16 weeks, then 10 mg or 5 mg BID. Upadacitinib should be dosed at 45 mg QD for 8 weeks or up to 16 weeks, and then at 30 mg or 15 mg in maintenance.

“Assess efficacy early,” he said, recommending symptom assessment at 2 weeks and checking fecal calprotectin at 4 to 6 weeks as well as repeating the lipid panel. And Dr Rubin stressed that for most patients, who will not have responded to anti-TNF, keeping the dosage at the higher level for maintenance will be necessary to achieve the best outcomes.

He concluded, “I think you’re going to be pleasantly surprised when you use these drugs in your patients.”

—Rebecca Mashaw

Rubin DT. JAK Inhibitors: Efficacy and Safety. Presented at: Advances in Inflammatory Bowel Diseases. Virtual.