New targeted Crohn’s therapy performs well in phase III trial

HONOLULU – Ustekinumab, a monoclonal antibody targeted against interleukins 12 and 23 (IL-12 and IL-23), met its primary endpoint for control of Crohn’s disease in a multinational phase III trial presented at the annual meeting of the American College of Gastroenterology.

The trial, called UNITI-2, enrolled patients with moderate to severe Crohn’s disease who had failed traditional therapies but were naive to or at least had not failed a tumor necrosis factor (TNF) inhibitor, reported Dr. Brian Feagan, professor of medicine, University of Western Ontario, London. Results of a second and parallel phase III trial with ustekinumab, called UNITI-1, which enrolled TNF inhibitor failures, have not yet been reported.

In UNITI-2, 628 patients were randomized to placebo, 130 mg of ustekinumab in a fixed subcutaneous dose of 130 mg, or a weight-based dose of 6 mg/kg of subcutaneous ustekinumab. Major enrollment criteria, other than failure of a non-TNF inhibitor therapy, included a Crohn’s disease activity index (CDAI) score between 220 and 450. The primary endpoint was a CDAI reduction of at least 100 points at 6 weeks. Clinical remission at 8 weeks, defined as CDAI less than 150, was a secondary endpoint.

The primary endpoint was reached by 28.7% randomized to placebo, 51.7% of those randomized to the fixed dose of ustekinumab, and 55.5% of those randomized to weight-based dosing. The advantage for the active treatment arms was statistically significant (both P less than .001). For the secondary endpoint of clinical remission at 8 weeks, the rates were 19.6% for placebo, 30.6% (P = .009 vs. placebo) for fixed-dose ustekinumab, and 40.2% (P less than .001 vs. placebo) for the weight-based dose.

The anti-inflammatory effect of ustekinumab, which inhibits signal transduction of IL-12 and IL-23 by binding to the p40 subunit that both cytokines employ for receptor binding, was reflected in the rapid reduction in C-reactive protein (CRP) concentrations observed with both doses but not with placebo, according to Dr. Feagan. He noted that the greater CRP reduction on the weight-based dosing, which nearly doubles ustekinumab exposure for some individuals, supports the dose-response anti-inflammatory mechanism of the drug.

Ustekinumab was well tolerated with similar rates and types of adverse events reported in the active treatment and placebo groups. This included infections, serious infections, and infusion reactions. There was a theoretical concern about an increased risk for cardiovascular events that was not substantiated in this study. No malignancies were observed in this short-term study.

Nearly 70% of the patients were naive to a biologic treatment. Of the 31.4% with prior exposure to a TNF inhibitor, none had met criteria for failure. About 80% had failed corticosteroids after what was considered to be an adequate course, while nearly 70% had failed one or more immunomodulators. About half had failed both.

Details about quality of life measures were not presented at the ACG, but Dr. Feagan said, summarizing the data, they “also confirmed the clinical efficacy of ustekinumab,” which was approved for the treatment of psoriatic arthritis more than 2 years ago.

The data, which suggest a level of efficacy comparable to other targeted therapies in Crohn’s disease, appear to encourage a filing for Food and Drug Administration approval in Crohn’s disease. However, data about the relative efficacy of this drug in those who have failed a TNF inhibitor is expected to provide greater insight about how this agent will add to current options.

“It is encouraging to see disease control with agents targeting novel cytokines in the inflammatory pathway, but we need to begin thinking about how these biologics fit with each other,” said Dr. David Rubin, chief, section of gastroenterology, hepatology, and nutrition, University of Chicago. Dr. Rubin was a moderator of the ACG session in which the UNITI-2 data were presented.

Dr. Feagan has financial relationships with Millennium, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, and many other pharmaceutical companies.

HONOLULU – Ustekinumab, a monoclonal antibody targeted against interleukins 12 and 23 (IL-12 and IL-23), met its primary endpoint for control of Crohn’s disease in a multinational phase III trial presented at the annual meeting of the American College of Gastroenterology.

The trial, called UNITI-2, enrolled patients with moderate to severe Crohn’s disease who had failed traditional therapies but were naive to or at least had not failed a tumor necrosis factor (TNF) inhibitor, reported Dr. Brian Feagan, professor of medicine, University of Western Ontario, London. Results of a second and parallel phase III trial with ustekinumab, called UNITI-1, which enrolled TNF inhibitor failures, have not yet been reported.

In UNITI-2, 628 patients were randomized to placebo, 130 mg of ustekinumab in a fixed subcutaneous dose of 130 mg, or a weight-based dose of 6 mg/kg of subcutaneous ustekinumab. Major enrollment criteria, other than failure of a non-TNF inhibitor therapy, included a Crohn’s disease activity index (CDAI) score between 220 and 450. The primary endpoint was a CDAI reduction of at least 100 points at 6 weeks. Clinical remission at 8 weeks, defined as CDAI less than 150, was a secondary endpoint.

The primary endpoint was reached by 28.7% randomized to placebo, 51.7% of those randomized to the fixed dose of ustekinumab, and 55.5% of those randomized to weight-based dosing. The advantage for the active treatment arms was statistically significant (both P less than .001). For the secondary endpoint of clinical remission at 8 weeks, the rates were 19.6% for placebo, 30.6% (P = .009 vs. placebo) for fixed-dose ustekinumab, and 40.2% (P less than .001 vs. placebo) for the weight-based dose.

The anti-inflammatory effect of ustekinumab, which inhibits signal transduction of IL-12 and IL-23 by binding to the p40 subunit that both cytokines employ for receptor binding, was reflected in the rapid reduction in C-reactive protein (CRP) concentrations observed with both doses but not with placebo, according to Dr. Feagan. He noted that the greater CRP reduction on the weight-based dosing, which nearly doubles ustekinumab exposure for some individuals, supports the dose-response anti-inflammatory mechanism of the drug.

Ustekinumab was well tolerated with similar rates and types of adverse events reported in the active treatment and placebo groups. This included infections, serious infections, and infusion reactions. There was a theoretical concern about an increased risk for cardiovascular events that was not substantiated in this study. No malignancies were observed in this short-term study.

Nearly 70% of the patients were naive to a biologic treatment. Of the 31.4% with prior exposure to a TNF inhibitor, none had met criteria for failure. About 80% had failed corticosteroids after what was considered to be an adequate course, while nearly 70% had failed one or more immunomodulators. About half had failed both.

Details about quality of life measures were not presented at the ACG, but Dr. Feagan said, summarizing the data, they “also confirmed the clinical efficacy of ustekinumab,” which was approved for the treatment of psoriatic arthritis more than 2 years ago.

The data, which suggest a level of efficacy comparable to other targeted therapies in Crohn’s disease, appear to encourage a filing for Food and Drug Administration approval in Crohn’s disease. However, data about the relative efficacy of this drug in those who have failed a TNF inhibitor is expected to provide greater insight about how this agent will add to current options.

“It is encouraging to see disease control with agents targeting novel cytokines in the inflammatory pathway, but we need to begin thinking about how these biologics fit with each other,” said Dr. David Rubin, chief, section of gastroenterology, hepatology, and nutrition, University of Chicago. Dr. Rubin was a moderator of the ACG session in which the UNITI-2 data were presented.

Dr. Feagan has financial relationships with Millennium, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, and many other pharmaceutical companies.

HONOLULU – Ustekinumab, a monoclonal antibody targeted against interleukins 12 and 23 (IL-12 and IL-23), met its primary endpoint for control of Crohn’s disease in a multinational phase III trial presented at the annual meeting of the American College of Gastroenterology.

The trial, called UNITI-2, enrolled patients with moderate to severe Crohn’s disease who had failed traditional therapies but were naive to or at least had not failed a tumor necrosis factor (TNF) inhibitor, reported Dr. Brian Feagan, professor of medicine, University of Western Ontario, London. Results of a second and parallel phase III trial with ustekinumab, called UNITI-1, which enrolled TNF inhibitor failures, have not yet been reported.

In UNITI-2, 628 patients were randomized to placebo, 130 mg of ustekinumab in a fixed subcutaneous dose of 130 mg, or a weight-based dose of 6 mg/kg of subcutaneous ustekinumab. Major enrollment criteria, other than failure of a non-TNF inhibitor therapy, included a Crohn’s disease activity index (CDAI) score between 220 and 450. The primary endpoint was a CDAI reduction of at least 100 points at 6 weeks. Clinical remission at 8 weeks, defined as CDAI less than 150, was a secondary endpoint.

The primary endpoint was reached by 28.7% randomized to placebo, 51.7% of those randomized to the fixed dose of ustekinumab, and 55.5% of those randomized to weight-based dosing. The advantage for the active treatment arms was statistically significant (both P less than .001). For the secondary endpoint of clinical remission at 8 weeks, the rates were 19.6% for placebo, 30.6% (P = .009 vs. placebo) for fixed-dose ustekinumab, and 40.2% (P less than .001 vs. placebo) for the weight-based dose.

The anti-inflammatory effect of ustekinumab, which inhibits signal transduction of IL-12 and IL-23 by binding to the p40 subunit that both cytokines employ for receptor binding, was reflected in the rapid reduction in C-reactive protein (CRP) concentrations observed with both doses but not with placebo, according to Dr. Feagan. He noted that the greater CRP reduction on the weight-based dosing, which nearly doubles ustekinumab exposure for some individuals, supports the dose-response anti-inflammatory mechanism of the drug.

Ustekinumab was well tolerated with similar rates and types of adverse events reported in the active treatment and placebo groups. This included infections, serious infections, and infusion reactions. There was a theoretical concern about an increased risk for cardiovascular events that was not substantiated in this study. No malignancies were observed in this short-term study.

Nearly 70% of the patients were naive to a biologic treatment. Of the 31.4% with prior exposure to a TNF inhibitor, none had met criteria for failure. About 80% had failed corticosteroids after what was considered to be an adequate course, while nearly 70% had failed one or more immunomodulators. About half had failed both.

Details about quality of life measures were not presented at the ACG, but Dr. Feagan said, summarizing the data, they “also confirmed the clinical efficacy of ustekinumab,” which was approved for the treatment of psoriatic arthritis more than 2 years ago.

The data, which suggest a level of efficacy comparable to other targeted therapies in Crohn’s disease, appear to encourage a filing for Food and Drug Administration approval in Crohn’s disease. However, data about the relative efficacy of this drug in those who have failed a TNF inhibitor is expected to provide greater insight about how this agent will add to current options.

“It is encouraging to see disease control with agents targeting novel cytokines in the inflammatory pathway, but we need to begin thinking about how these biologics fit with each other,” said Dr. David Rubin, chief, section of gastroenterology, hepatology, and nutrition, University of Chicago. Dr. Rubin was a moderator of the ACG session in which the UNITI-2 data were presented.

Dr. Feagan has financial relationships with Millennium, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, and many other pharmaceutical companies.