AIBD 2010: Promising New Biologics in Development to Treat IBD

Novel biologics in development may provide alternatives to current standards of care and aid in treating patients with refractory inflammatory bowel disease (IBD), however, practicing clinicians should optimize therapy using currently available agents, according to research presented at the 2010 Advances in Inflammatory Bowel Diseases, the Crohn's & Colitis Foundation's Clinical & Research Conference, being held December 9-12 in Hollywood, FL.

During a session focusing on future directions in basic and clinical research, Jean-Frederic Colomebel, MD, of the Centre Hospitalier Universitaire (CHU) de Lille in France, discussed new biologics in development to address the treatment of IBD, providing insight into the most anticipated agents, those that appear to be disappointing, and those with niche applications.

Vedolizumab (MLN-0002) is a novel monoclonal antibody undergoing investigation in both Crohn’s disease (CD) and ulcerative colitis (UC). In a clinical trial evaluating 181 patients with active UC, administration of vedolizumab resulted in a higher rate of remission at week six than among those who received placebo. A follow-up trial in patients with CD failed to meet the defined primary end point, which was percentage of clinical response at day 57, but the higher of the two dose groups was significantly better as compared with placebo. Currently, phase III trials are underway in both UC and CD to evaluate the efficacy and long-term safety of this agent.

Another agent being investigated in CD is CCX282-B, which in a clinical trial involving 436 patients with active CD maintained remission over 36 weeks and was well tolerated. However, during the induction phase of the study, the drug did not meet the primary endpoint of CD Activity Index (CDAI) response 70 at week eight. Two other agents in development, ustekinumab (CNTO 1275) and briakinumabe (Anti-interleukin [IL] 12/23p40; ABT874), are monoclonal antibodies targeting IL-12 and IL-23. In a phase IIb, multi-center, randomized, double-blind, parallel group, placebo-controlled dose ranging study, investigators evaluated the efficacy of briakinumab during a 12-week induction phase, 12-week maintenance phase, and open label phase for patients who did not respond or who relapsed during maintenance phase. The investigators found remission improved with briakinumab at weeks six and 12 as compared with placebo. CDAI 100 response at weeks six and 12 was also improved as compared to placebo.

In another study evaluating the efficacy of ustekinumab in CD, investigators found that the clinical response through week eight was improved with the drug as compared to placebo. In addition, among patients with a prior infliximab clinical response, the use of ustekinumab improved clinical response through week eight in active CD patients as compared to placebo. The drug was also shown to decrease C-reactive P levels in the overall group and the subset of prior responders to infliximab.

While some drugs have shown efficacy in other diseases such as rheumatoid arthritis, their efficacy in IBD remains limited. Drugs that have failed to be effective in CD and/or UC include abatacept, visilizumab, and rituximab. Other agents with the potential to be effective in IBD include those that target IL-6 and IL-17 and some small molecules. Tocilizumab is an agent that targets IL-6 and is currently undergoing Phase II study in CD. AIN457 and AMG827 are anti-IL17 monoclonal antibodies undergoing investigation in severe, active CD, with results anticipated for 2011. Another innovative biological strategy is TNF-alpha kinoid (TNF-K-005), which is an anti-TNF vaccination therapy that is currently undergoing phase IIa investigation.

In terms of small molecules, laquinimod, a JAK3/gc inhibitor, has been shown to be potent and efficacious in various animal models of inflammatory autoimmune diseases such as multiple sclerosis, IBD, lupus, rheumatoid arthritis, type II diabetes, and Guillain—Barré Syndrome. Although there appears to be a number of biologics and small molecules in development, many of them are in earlier phases of development, and Colomebel recommends that practicing clinicians should optimize therapy with currently available agents.