AG011 for Inflammatory Bowel Disease
Ulcerative colitis and Crohn’s disease, known collectively as inflammatory bowel disease (IBD), currently affect 0.5-1% of the Western world’s population. This translates to over one million people in the USA (525,000 ulcerative colitis patients; 490,000 Crohn's disease patients) and four million people worldwide. Patients experience a range of gastrointestinal symptoms, including diarrhea, rectal bleeding and abdominal pain, resulting in weight loss as well as other extra intestinal manifestations such as skin and eye disorders. Because IBD is a chronic disease, patients generally require lifelong treatment. The market of IBD products is estimated to be more than US$2 billion and is still growing, partly due to the introduction of new therapies such as monoclonal antibodies.
ActoGeniX’s lead product for IBD, AG011, is an ActoBiotic™ delivering human Interleukin-10 (IL-10). IL-10 is an important signaling molecule (cytokine) that plays a critical role in the immune system. It has powerful anti-inflammatory properties and acts as a central factor in the induction and maintenance of immune tolerance. IL-10 was discovered many years ago but to date its therapeutic potential has not been exploited fully. Indeed, while clinicians have in recent years evaluated systemically injected IL-10 in both Crohn’s disease as well as ulcerative colitis patients, they found it to be only modestly effective when delivered in this way. This is most likely due to limited bioavailability of injected IL-10 in the gastrointestinal tissues and to its short half-life in the circulatory system. In addition, high doses of injected IL-10 were shown to have significant side effects, limiting the dosing that could be tested.
| Systemically injected IL-10 | AG011 |
|---|---|
Invasive delivery (injection) |
Oral administration |
Short serum half-life, unstable in the circulatory system |
Sustained delivery over 6-24 hours by Lactococcus |
Systemic exposure resulting in significant adverse events |
Local and targeted delivery without systemic exposure |
High doses required, resulting in side effects |
Limited amounts of IL-10 delivered locally |
Induction of pro-inflammatory cytokines |
Anti-inflammatory action and induction of regulatory T cells |
Low GI tissue bioavailability |
Local delivery resulting in good GI tissue penetration |
ActoGeniX designed AG011, which fully exploits the inherent powerful immuno-regulatory properties of IL‑10. At the same time, AG011 overcomes the drawbacks associated with an injectable formulation: it delivers IL-10 directly at its desired site of action in the GI tract, avoiding unnecessary systemic circulation. Based on these characteristics, AG011 is expected to be highly efficacious but also devoid of the side effects associated with systemic IL-10.
ActoGeniX is currently conducting a Phase 2 clinical trial with AG011 in ulcerative colitis patients, and plans to start a Phase 2 trial in Crohn’s disease patients during 2009. If successful, AG011 could be the first oral protein drug available for IBD. It is expected to deliver excellent efficacy together with a favorable safety profile. Hence, AG011 has the potential to become first-line therapy for Crohn’s disease and ulcerative colitis.