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New treatments for IBD show efficacy in trials; Annual Digestive Diseases Week.

NEW ORLEANS -- Several drugs showed efficacy in patients with inflammatory bowel disease in reports at the annual Digestive Diseases Week:

* Adalimumab. Results from a phase III study showed that adalimumab (Humira), which already has Food and Drug Administration approval to treat rheumatoid arthritis, was effective for inducing remission in patients with moderately to severely active Crohn's disease, Dr. Stephen B. Hanauer said at the meeting.

"The results are very similar to infliximab, but adalimumab can be self-administered" by subcutaneous injection, said Dr. Hanauer, chief of the section of gastroenterology at the University of Chicago. Infliximab requires intravenous administration.

Adalimumab is a fully human monoclonal antibody that, like infliximab, blocks tumor necrosis factor. The study was sponsored by Abbott Laboratories Inc., which markets Humira; Dr. Hanauer has been a consultant to Abbott.

The study enrolled 299 patients whose Crohn's disease had not responded to treatment with an aminosalicylate, steroids, or immunomodulator drugs. They were randomized to one of four treatment groups: an initial subcutaneous injection of 40 mg of adalimumab followed by a second, 20-mg injection after 2 weeks; an initial 80-mg injection of adalimumab followed by a 40-mg injection after 2 weeks; an initial 160-mg injection of adalimumab followed by an 80 nag injection after 2 weeks; or two placebo injections.

The study's primary end point was the rate of remission produced by the two highest dosages compared with placebo at 4 weeks after the start of treatment. Remission was defined as a score lower than 150 points on the patient's baseline Crohn's Disease Activity Index (CDAI). A secondary end point was response rate, defined as a drop of at least 70 points in the CDAI score.

Enrolled patients had CDAI scores of 220 450 at baseline, with an average score of about 300.

At 4 weeks after treatment began, the 151 patients in the groups receiving the two highest dosages had a 30% remission rate, compared with 12% in the 74 patients treated with placebo, a statistically significant difference. Remission was achieved in 36% of the patients in the high-dosage group, 24% of those in the middle-dosage group, and 18% of those in the low-dosage group. (See table.)

A 70-point or better response occurred in 54% of patients in the low-dosage group, 59% of those in the middle-dosage group, and 60% of those in the high-dosage group, compared with a 37% rate in the placebo group.

Adalimumab was well tolerated. Serious adverse events occurred in three patients treated with placebo and four patients treated with adalimumab.

The results "raised no new safety concerns, and adalimumab has already been given to more than 50,000 patients with rheumatoid arthritis," Dr. Hanauer said. Results from prior studies showed that a small number of patients treated with adalimumab developed disseminated tuberculosis, other serious infections, or sepsis.

A study that is examining adalimumab's efficacy for maintaining responses in patients with Crohn's disease is ongoing, Dr. Hanauer said.

* OPC-6535. This still unnamed drug is a thiazole derivative that inhibits super-oxide production, cytokine production, and endothelial adhesion of neutrophils and monocytes. The drug is administered orally, and is an inhibitor of phosphodiesterase 4, which appears only in immune cells, the brain, and the lungs. The study was sponsored by Otsuka Maryland Research Institute Inc., which developed OPC-6535. The study's principle investigator, Dr. Hanauer, is a consultant to Otsuka and heads the company's advisory board for development of this drug.

The phase II study results reported at the meeting involved 186 patients with active ulcerative colitis and disease activity index scores of 4-11 (on a scale of 0-12); the average activity index was 7.45. Patients were allowed to be on concurrent treatment with 5-aminosalicylic acid if the dosage was stable for at least 14 days before they entered the study and remained stable throughout the study.

Patients were randomized to treatment with either 25 mg or 50 nag of OPC-6535 per day, or placebo. Treatment continued for 8 weeks. The study's primary end point was the percentage of patients who achieved at least a 3 point drop in their disease activity index scores. Secondary end points were the mean change in the disease activity index and the rate of remission, which was defined as a disease activity index score of 0 or 1.

After 8 weeks, the percentage of patients with at least a 3-point drop in their disease activity index scores was 40% in those on placebo, 55% in those on the 25-mg dosage, and 48% in those on the 50-mg dosage. The difference between the treatment and controls groups was not statistically significant, Dr. Hanauer said.

The average change in disease activity index scores was 1.5 in the placebo group and 2.8 in each of the treatment groups. There was a significant difference between the 25-mg group and the placebo patients, but not between the 50-mg and the placebo groups. Other measures of efficacy, including the remission rate, were not significantly different between the placebo and active treatment groups.

The apparent reason for the lack of significant differences was the number of patients who dropped out of the study, which cut the statistical power of the intention to treat analysis. A total of 64 patients dropped out--23 in the placebo group, 14 in the 25-mg group, and 27 in the 50 mg group. About half the patients dropped out because of adverse effects, and about a quarter dropped out because of ulcerative colitis symptoms. The most common drug-related adverse effects were headache and nausea; these were reduced if patients were started on a low dosage that was gradually increased over 1 week to the target level, Dr. Hanauer said.

A post hoc analysis that focused only on patients who entered the study with a disease activity index score of at least 7 suggested that the drug had a more dramatic effect on patients with more severe symptoms. In this subanalysis with 113 patients, the remission rate was 3% in the placebo group, 13% in the 25-mg group, and 18% in the 50-mg group, a statistically significant difference vs. placebo.

Phase III studies testing the use of the drug to treat ulcerative colitis are in progress, Dr. Hanauer said. These studies are using remission as the primary end point.

* Fontolizumab. Fontolizumab is a humanized, monoclonal antibody to interferon-[gamma] that is administered by intravenous infusion. Interferon-[gamma] is involved in the development of T helper cells and the activation of other immune cells, and it appears to play a role in the pathogenesis of Crohn's disease.

A phase II study enrolled 133 patients with moderately to severely active Crohn's disease. Patients had CDAI scores of 250-450, with an average score of about 300. The study, done at 25 centers in Europe, was sponsored by Protein Design Labs Inc., which makes fontolizumab (HuZAF). The principal investigator, Dr. Daniel W. Hommes, a gastroenterologist at the Academic Medical Center in Amsterdam, is a consultant to Protein Design Labs.

The first 42 patients in the study were randomized to receive a single, intravenous infusion of either 4 mg/kg or 10 mg/kg fontolizumab, or placebo. The next 91 patients in the study received a second infusion with the same amount of drug 28 days after their first treatment.

The study's primary end point was the rate of remission or response to the first dose after 28 days. The remission rate (defined as a CDAI score lower than 150) was 12% in the control group, 31% in the 4 mg/kg group, and 19% in the 10 mg/kg group. The difference between the low dosage and placebo groups was statistically significant, Dr. Hommes said. The response rate (defined here as a drop in the CDAI score of at least 100 points) was 33% in the placebo group, 38% in the low-dosage group, and 44% in the high-dosage group; none of the between group differences was statistically significant.

Among the 91 patients who received two doses, the response rates after 56 days were 35% in the placebo group, 69% in the low-dosage group, and 67% in the high-dosage group. The remission rates were 29% in the placebo group, 40% in the low dosage group, and 58% in the high-dosage group. The rates in the drug-treated groups were significantly greater than those in the control group.

Five patients had serious adverse effects: one in the placebo group, three in the 4-mg/kg group, and one in the 10-mg/kg group.

* Basiliximab. Basiliximab (Simulect) is a chimeric mouse-human monoclonal antibody that blocks the cellular receptor for the cytokine interleukin 2. It is marketed by Novartis AG and is approved by the FDA to prevent organ rejection in renal transplant patients.

The drug's efficacy as a steroid sensitizer in patients with moderately or severely active ulcerative colitis was assessed in a pilot, uncontrolled study with 30 patients that was sponsored by Novartis. The study included 20 patients with moderate disease and a disease score of at least 6, despite at least 14 days of treatment with at least 30 mg of prednisolone per day, and 10 patients with severe disease who had an incomplete response to intravenous treatment with 400 mg of hydrocortisone per day.

All patients received a single intravenous dose of 40 nag of basiliximab along with their standard steroid therapy. Of the patients with moderate disease, 14 achieved full remission within 8 weeks after basiliximab treatment, and 5 additional patients had improved disease activity scores, said Dr. Tom J. Creed of the University of Bristol (England). The one remaining patient in this group did not respond and required treatment with cyclosporin.

Of the 10 patients with severe disease, 5 achieved remission and 5 required colectomy. The usual course of severe, steroid unresponsive ulcerative colitis is that 85% of patients need colectomy within a similar follow-up period, Dr. Creed said.

About 67% of the patients who achieved remission 8 weeks after basiliximab treatment were still in remission at 24 weeks after treatment. There were no infusion reactions, but two patients developed herpes zoster.

A randomized, controlled study with a larger number of patients is now needed. Dr. Creed said.
Adalimumab's Effect on Active Crohn's Disease
After 4 Weeks of Treatment

                                                             160 mg/
                          Placebo  40 mg/20 mg  80 mg/40 mg   80 mg

Number of patients          74         74           75         76
Percent of
patients with remission     12%        18%          24%        36%
Percent of
patients with response *    37%        54%          59%        60%

At least a 70-point drop in CDAI score.

Source: Dr. Stephen B. Hanauer


Philadelphia Bureau
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Title Annotation:Rx; inflammatory bowel disease
Author:Zoler, Mitchel L.
Publication:Family Practice News
Article Type:Brief Article
Geographic Code:1USA
Date:Jul 1, 2004
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