Biologic therapies lead evolution of Crohn's treatments

May 22, 2006

LOS ANGELES (May 22, 2006) - A variety of diseases are now treated with biologic therapies, which are derived from human tissues, because of their ability to target specific causes of inflammation compared with the general immunosuppressive effects of the chemical-based compounds that make up current therapies. In research presented today at Digestive Disease Week¢ç 2006 (DDW), several biologic therapies are successfully demonstrating remission of moderate to severe Crohn's disease, which is often unresponsive to conventional therapy. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

The studies below assess therapies for patients with moderate to severe Crohn's disease, which is measured as scores on the Crohn's Disease Activity Index (CDAI) of between 220 and 450. CDAI is a score of eight factors used to assess a patient's wellness, including the daily number of liquid or very soft stools, severity of abdominal pain, level of general well-being and other measures. A score of less than 150 is generally considered remission.

Adalimumab Induces and Maintains Clinical Response and Remission in Patients With Active Crohn's Disease: Results of the CHARM Trial [Abstract 686d]

Because of the similar inflammatory proteins that are increased in patients with arthritis and Crohn's disease (CD), many research teams are performing trials of arthritis medicines to evaluate their benefit for GI diseases. This study reviews the efficacy and safety of maintenance therapy for active Crohn's patients with the use of adalimumab, a fully human monoclonal antibody, which is already approved for treatment of rheumatoid arthritis and psoriatic arthritis.

Adalimumab (ADA), which has previously shown positive results for inducing remission in CD, was evaluated for maintaining remission in this double-blind, placebo-controlled, multi-center, 56-week study in patients with moderately to severely active CD. The team compared two ADA dosing regimens in maintaining clinical remission (CDAI<150) at 26 and 56 weeks in patients with active disease who had already responded to open-label (OL) induction therapy with ADA.

A total of 854 patients received OL induction with ADA. After four weeks of treatment, half of the patients (n=499) who had achieved clinical response (CDAI decrease ¡Ã70 from baseline) were randomized to receive placebo, ADA every other week (EOW), or ADA weekly (W) through week 56. The other half remained on therapy. Patients with active fistulas, or openings in the colon, at both screening and baseline visits were assessed for fistula closure.

Significantly higher rates of remission and response were maintained with ADA versus placebo (46 percent vs 17 percent remission, and 52 percent vs 26 percent response at week 26, respectively). Maintenance ADA therapy also significantly increased the number of patients with steroid-free remission compared to placebo (35 percent vs. 3 percent at week 26) as well as complete fistula closure (36 percent vs 14 percent). Overall, the ADA safety profile was consistent with previous reports of studies using ADA and other anti-TNF agents.

"We are confident that based on the results of this study, adalimumab use weekly or bi-monthly effectively maintains clinical remission and response, steroid-free remission, and fistula closure in patients with moderately to severely active CD," said Jean-Frederic Colombel, M.D., Centre Hospitalier Universitaire de Lille in France and lead study author. "We hope that continued trials will confirm the strong tolerability profile of adalimumab and offer patients another reliable option to manage their symptoms."

Certolizumab Pegol Administered Subcutaneously is Effective and Well Tolerated in Patients with Active Crohn's Disease: Results From a 26-Week, Placebo-Controlled Phase III Study (PRECiSE 1) [Abstract 745]

To further evaluate the opportunities to work with biologic therapies for hard-to-treat diseases, researchers are focusing on improving convenience and reducing the risk of allergic side effects to maximize the benefit of the therapy while reducing drug intolerence. In this study, researchers examine a humanized monoclonal antibody, certolizumab pegol (CDP870), and -found positive efficacy and tolerability results for patients suffering from Crohn's disease.

The phase III multi-center study randomized adult patients with moderate to severe Crohn's disease to receive certolizumab pegol or placebo at weeks 0, 2, 4 and then every four weeks until week 24. The patients were divided into two groups according to their baseline C-reactive protein levels (CRP <10mg>The researchers measured response to the therapy at regular intervals throughout the study and at withdrawal, including clinical response (decrease in CDAI ¡Ã100) in patients with CRP ¡Ã10mg/L and remission (CDAI ¡Â150) in the CRP ¡Ã10mg/L stratum, as well as change in CRP levels in both populations.

Certolizumab pegol patients enjoyed significantly better response to therapy in the CRP ¡Ã10mg/L group compared to the placebo (33 percent vs 20 percent at week four and 37 percent vs 26 percent at week 6). Remission and long-term response was also significantly higher for certolizumab pegol users (20 percent vs 10 percent at week four), and this group experienced a greater reduction in CRP levels. Overall, the drug was well tolerated by the study patients.

"Certolizumab pegol demonstrated positive results and good tolerability in this study of patients with active moderate to severe Crohn's disease," said William Sandborn, M.D., of the Mayo Clinic and lead study author. "This is the largest long-term induction study of a biologic agent performed to date in CD, and we believe it yields promising results for patients with this disease whose symptoms may not be improving with current standard therapies."

Natalizumab Induces Sustained Response and Remission in Patients with Active Crohn's Disease: Results from the ENCORE Trial [Abstract 747]

To counteract the chronic inflammation of Crohn's disease, recent research has focused on new therapies to induce a measurable and sustained response in patients with moderate to severe symptoms. In this phase III trial, researchers found successful results with the use of natalizumab therapy for up to eight weeks. Natalizumab (Tysabri¢ç), is a monoclonal antibody, which interferes with the immune response that causes inflammation in Crohn's disease.

ENCORE (Efficacy of Natalizumab in Crohn's Disease Response and Remission) evaluated the effects of natalizumab in Crohn's patients with active inflammation (C-reactive protein [CRP] levels greater than the highest normal rating of 2.87 mg/L). More than 500 patients were randomized to receive natalizumab (n=259) or placebo (n=250) infusions at weeks 0, 4 and 8. The researchers measured for efficacy and side effects after 4, 8 and 12 weeks, with the hope of achieving a sustained clinical response (¡Ã 70 point decrease in baseline CDAI score) or remission (CDAI < 150).

The team found promising results with the use of natalizumab. A significantly higher proportion of patients in the natalizumab group responded to therapy at weeks 8 and 12 compared to patients in the placebo group (48 percent vs. 32 percent). Half of patients receiving natalizumab responded after the first infusion (51 percent) compared to one-third (37 percent) in the placebo group, and the response rate in the treated group was sustained at all points during the trial. More than 25 percent of natalizumab patients achieved remission at weeks 8 and 12, compared to just 16 percent of the placebo group. Incidence and adverse events were similar between the groups.

"These results demonstrate that natalizumab induced early and sustained response and remission in patients with active Crohn's disease," said Stephan Targan, M.D., of Cedars-Sinai Medical Center and lead study author. "We believe this trial confirms the benefit of this therapy along with its safe use as an induction therapy for Crohn's patients, and may be a better option for treating moderate to severe symptoms."

A Safety Evaluation for Progressive Multifocal Leukoencephalopathy (PML) in Greater Than 3,500 Patients with Crohn's Disease (CD), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA) Previously Treated with Natalizumab in Clinical Trials [Abstract 492]

Natalizumab, a humanized monoclonal antibody approved to treat multiple sclerosis (MS) in 2004, was in trials for the treatment of Crohn's disease (CD) and rheumatoid arthritis (RA). Clinical trials for the product were suspended in February 2005 after two patients experienced PML (progressive multifocal leukoencephalopathy) while on combination therapy with natalizumab and ¥â interferon. Subsequently, a third case was identified in a patient with Crohn's disease who was receiving natalizumab and previously had received combination therapy with natalizumab and azathioprine. A safety evaluation was performed in all patients who had been recently treated with natalizumab to screen for PML and determine a more accurate estimate of the actual incidence of the event. PML is a rare disorder of the nervous system that affects individuals with suppressed immune systems and is detected by a JC virus (a brain infection damaging nerve cells and causing mental deterioration which may be fatal, named for a patient first diagnosed with the disease).

The evaluation included a physical exam, referral to a neurologist, brain MRI and analysis of cerebral spinal fluid (CSF) and serum for JC virus. An independent expert committee reviewed all suspected cases of PML and made final determinations of whether the patient had PML. In addition to patients from clinical trials, four post-marketing reports of suspected PML were also referred to the committee.

Enrollment in the safety evaluation was high, including 87 percent (1,275), 91 percent (2,248) and 92 percent (296) of all eligible study participants with Crohn's disease, multiple sclerosis and rheumatoid arthritis, respectively. CSF was analyzed for JC virus in 6 percent of CD, 16 percent of MS, and 4 percent of RA patients, and plasma in 88 percent of CD, 56 percent of MS, and 95 percent of RA patients. No additional cases were found to have PML, and the four post-marketing cases referred to the committee were also judged not to have PML.

"Results of this analysis suggest that the absolute risk of developing PML during therapy with natalizumab is very low," said William Sandborn, M.D., of the Mayo Clinic and lead study author. "We believe that natalizumab is still of great benefit to patients with moderate to severe Crohn's disease, so that potential benefit in selected patients needs to be carefully weighed against the small risk of PML."
Digestive Disease Week¢ç (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 20-25, 2006 in Los Angeles, California. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.

American Gastroenterological Association

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