JAK Inhibitors in IBD: Positioning is Key

Tofacitinib is a new small molecule agent, also known as a Janus kinase or JAK inhibitor, that when positioned and used for the right indication, can be effective against ulcerative colitis (UC), according to a presentation at the 2018 AIBD Meeting.  

“We need to know all we can on how to get the best and most of it,” Dr Bruce Sands, Chief of the Dr. Henry D. Janowitz Division of Gastroenterology and the Dr. Burrill B. Crohn Professor of Medicine at Icahn School of Medicine at Mount Sinai, said during his presentation.

Currently, standard dosing of tofacitinib consists of an induction dose of 10 mg po BID for 8 weeks. Patients considered nonresponders at 8 weeks should undergo 8 more weeks of tofacitinib.

Maintenance therapy for TNF-naïve responders should maintain therapy at 5 mg BID, whereas 10 mg BID should be considered in TNF-IR responders. Dose adjustments for renal or liver impairment should also be considered.

The dosages are indicative of results from the OCTAVE clinical trials, in which tofacitinib was superior to placebo in patients with UC.

Tofacitinib is achieving rates of roughly 30% compared to 11% to 15% with placebo at induction phase,” Sands said.

In the trials, among patients who do not achieve clinical response by 8 weeks, if there is no urgent reason to stop treatment, then Sands suggests trying another 8 weeks of tofacitinib.

Sands noted that although patients previously exposed to TNF have experienced lower absolute rates of response and remission, tofacitinib still produces responses in this patient population.

The safety profile of tofacitinib was consistent, with increased rate of herpes zoster (5%) with the 5 mg maintenance dose.

“If we look specifically at infections, serious events were rare events,” Sands said. “For the most part, herpes zoster was the most common, and it was non-serious herpes zoster.”

Compared with anti-TNFs, rates of herpes zoster were lower with anti-TNFs than tofacitinib. Therefore, there is a clear higher risk for herpes zoster with higher dose of tofacitinib.

Other adverse events worth noting included increased non-melanoma skin cancer, LDL and HDL cholesterol increased with no cardiovascular impact, gastrointestinal perforation risk was not increased over placebo, no immunogenicity, and little data on pregnancy exists.

“In the studies, events that were serious enough to warrant decrease in dose or discontinuation were extremely rare, but it is something to look for,” Sands said.

Monitoring certain laboratory variables will be important in patients receiving or considering therapy with tofacitinib. These include:

• lymphocytes at baseline and every 3 months;
• neutrophils at baseline, 4-8 weeks, and every 3 months;
• hemoglobin at baseline, 4-8 weeks, and every 3 months; and
• Lipids every 4-8 weeks.

Sands said lipids should be checked at least once after initiation of therapy.

Routine monitoring of liver function is also recommended to identify elevated liver enzymes to avoid drug-induced liver injury.

Tofacitinib is a new small molecule agent, also known as a Janus kinase or JAK inhibitor, that when positioned and used for the right indication, can be effective against ulcerative colitis (UC), according to a presentation at the 2018 AIBD Meeting.  

“We need to know all we can on how to get the best and most of it,” Dr Bruce Sands, Chief of the Dr. Henry D. Janowitz Division of Gastroenterology and the Dr. Burrill B. Crohn Professor of Medicine at Icahn School of Medicine at Mount Sinai, said during his presentation.

Currently, standard dosing of tofacitinib consists of an induction dose of 10 mg po BID for 8 weeks. Patients considered nonresponders at 8 weeks should undergo 8 more weeks of tofacitinib.

Maintenance therapy for TNF-naïve responders should maintain therapy at 5 mg BID, whereas 10 mg BID should be considered in TNF-IR responders. Dose adjustments for renal or liver impairment should also be considered.

The dosages are indicative of results from the OCTAVE clinical trials, in which tofacitinib was superior to placebo in patients with UC.

Tofacitinib is achieving rates of roughly 30% compared to 11% to 15% with placebo at induction phase,” Sands said.

In the trials, among patients who do not achieve clinical response by 8 weeks, if there is no urgent reason to stop treatment, then Sands suggests trying another 8 weeks of tofacitinib.

Sands noted that although patients previously exposed to TNF have experienced lower absolute rates of response and remission, tofacitinib still produces responses in this patient population.

The safety profile of tofacitinib was consistent, with increased rate of herpes zoster (5%) with the 5 mg maintenance dose.

“If we look specifically at infections, serious events were rare events,” Sands said. “For the most part, herpes zoster was the most common, and it was non-serious herpes zoster.”

Compared with anti-TNFs, rates of herpes zoster were lower with anti-TNFs than tofacitinib. Therefore, there is a clear higher risk for herpes zoster with higher dose of tofacitinib.

Other adverse events worth noting included increased non-melanoma skin cancer, LDL and HDL cholesterol increased with no cardiovascular impact, gastrointestinal perforation risk was not increased over placebo, no immunogenicity, and little data on pregnancy exists.

“In the studies, events that were serious enough to warrant decrease in dose or discontinuation were extremely rare, but it is something to look for,” Sands said.

Monitoring certain laboratory variables will be important in patients receiving or considering therapy with tofacitinib. These include:

• lymphocytes at baseline and every 3 months;
• neutrophils at baseline, 4-8 weeks, and every 3 months;
• hemoglobin at baseline, 4-8 weeks, and every 3 months; and
• Lipids every 4-8 weeks.

Sands said lipids should be checked at least once after initiation of therapy.

Routine monitoring of liver function is also recommended to identify elevated liver enzymes to avoid drug-induced liver injury.