JAK Inhibitor Shows Efficacy in Active Ulcerative Colitis

Caroline Helwick

June 01, 2011

June 1, 2011 (Chicago, Illinois) — The novel oral immunomodulatory agent tofacitinib appears to be promising, at least in the highest doses, according to a multicenter phase 2 study of 200 patients with ulcerative colitis.

"The drug worked fairly quickly in ulcerative colitis. There were dose-related improvements and it was well tolerated," William J. Sandborn, MD, from the University of California at San Diego Medical Center, reported here at Digestive Disease Week 2011.

Tofacitinib is a novel oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator. The drug inhibits JAK1, 2, and 3 in vitro, and has functional specificity for JAK1 and JAK3 over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important set of proinflammatory cytokines, including interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which have a number of effects on the immune system and inflammatory cascade, according to Dr. Sandborn.

"We conducted this study as a proof of concept to evaluate dose response and to look for trends in patients with moderate to severe active disease," Dr. Sandborn noted at a distinguished abstracts plenary session. He indicated that a large proportion of the study population could be considered to have failed optimal treatment regimens.

The results were some of the first efficacy findings for tofacitinib in a condition other than rheumatoid arthritis, Dr. Sandborn noted. The fact that the drug is delivered orally, and not injected as is typical for other biologics in inflammatory diseases, is considered an attractive feature.

The study was a multicenter double-blind phase 2 trial of 194 patients with moderate to severe ulcerative colitis (excluding those with proctitis), a Mayo score of 6 or higher, and an endoscopic subscore of 2 or higher. Mean disease duration was approximately 9 years, and mean Mayo score was approximately 8. Previous treatment included aminosalicylates, immunosuppressants, steroids, and tumor necrosis factor (TNF) inhibitors.

Patients were randomized (in a 2:2:2:3:3 ratio) to tofacitinib 0.5, 3.0, 10.0, or 15.0 mg twice daily or to placebo twice daily for 8 weeks. Stable background treatments for ulcerative colitis were permitted, except for immunosuppressants and TNF inhibitors.

The primary end point was clinical response rate (decrease in Mayo score of 3 points or more and a 30% or more reduction in symptoms; a decrease in rectal bleeding subscore of 1 point or more, or an absolute subscore of 1 or less) at week 8. Secondary end points included clinical remission rate (Mayo score of 2 or less and no subscore above 1), endoscopic remission (an endoscopic subscore of 0), and endoscopic response (a decrease in endoscopic subscore of 1 or more) at week 8. Percent change from baseline in fecal calprotectin and C-reactive protein was also measured.

Primary Efficacy End Point Was Met

Tofacitinib treatment resulted in significant differences, compared with placebo, in clinical response rates at week 8. Clinical responses were noted in only 38.1% of placebo patients, compared with 76.3% of those in the tofacitinib 15.0 mg group, 65.0% of those in the 10.0 mg group, 46.1% of those in the 3.0 mg group, and 39.4% of those in the 0.5 mg group, Dr. Sandborn reported.

Endoscopically, just 2.0% of the placebo group was in remission, compared with 30.3% of the tofacitinib 10 mg group.

Clinical and Endoscopic Response and Remission Rates at Week 8

Level of Achievement Placebo
(n = 48)
0.5 mg
(n = 31)
3.0 mg
(n = 33)
10.0 mg
(n = 33)
15.0 mg
(n = 49)
Clinical response, % 41.7 32.3 48.5 60.6 77.6
Clinical remission, % 10.4 12.9 33.3 48.5 40.8
Endoscopic response, % 45.8 51.6 57.6 66.7 77.6
Endoscopic remission, % 2.1 9.7 18.2 30.3 26.5

Significant differences in mean partial Mayo scores, compared with placebo, were observed at week 8 with tofacitinib 10.0 mg (P = .010) and 15.0 mg (P < .001). "This difference was observed as early as week 2," he noted.

A mean change of 60 points was observed in almost 50% of patients receiving the highest dose, compared with just 26.5% receiving placebo. "A meaningful increase is anything over 16 points," he pointed out. "This is quite a striking effect on the IBDQ [Inflammatory Bowel Disease Questionnaire]."

In parallel, patients treated with the higher doses of tofacitinib demonstrated a marked — more than 50% — reduction from baseline in fecal calprotectin, whereas placebo-treated patients demonstrated small changes, he added.

The overall incidence of adverse events and serious adverse events were similar between tofacitinib- and placebo-treated patients. There was, however, a dose-dependent increase from baseline to week 8 in levels of low-density lipoprotein (LDL), which rose nearly 12 mg/dL in the 15.0 mg group and 9 mg/dL in the 10.0 mg group. Levels of triglyceride rose by 16.5 mg/dL with the highest dose, and high-density lipoprotein (HDL) rose by 12 mg/dL. There were few to no changes in lipid parameters in the placebo group.

"A change in lipid profile was observed over time. There was a dose-dependent rise in LDL, HDL, and triglycerides. These went back to baseline levels during the washout phase (weeks 8 to 12)," Dr. Sandborn explained, noting that patients can be effectively treated with statins. He added: "Speaking as someone who takes a statin, I think these are small risks." No clinically significant changes were observed in other laboratory data.

Maria T. Abreu, MD, chief of gastroenterology at the University of Miami Miller School of Medicine in Florida, moderated the session and commented on the findings to Medscape Medical News.

"The data on the JAK inhibitor are really remarkable. These findings look similar to the anti-TNF trials in Crohn's disease — the differences are enormous," Dr. Abreu said. Should subsequent findings look as promising, this agent could offer another avenue of much-needed treatment in an area that "has been lagging behind in new therapies," she added.

The study was funded by Pfizer. Dr. Sandborn reports receiving consulting fees from ActoGeniX, AGI Therapeutics, Alberio AB, AM-Pharma BV, Amgen, Astellas Pharma, Athersys, Atlantic Healthcare Limited, Axcan Pharma, BioBalance, Celgene Corporation, Celek Pharmaceuticals LLC, Cellerix SL, Chemocentryx, CoMentis, Cosmo Technologies, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Co. Ltd, Enteromedics, and Ferring Pharmaceuticals; and receiving grant/research support from Abbott, Bristol-Myers Squibb, Centocor, and Elan Pharmaceuticals. Dr. Abreu has disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2011: Abstract 594. Presented May 8, 2011.


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