Crohn’s disease and ulcerative colitis are two chronic inflammatory bowel diseases. Many patients either don’t respond or develop side effects with current treatments. There is an urgent need for new treatments and cure.

Will targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis, lead to safe, effective treatments in Crohn's and colitis?

The rapid recruitment and retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. Our group has been involved in  several large randomised controlled trials  exploring efficacy and safety of targeting leukocyte homing and adhesion in the gut mucosa. Leucocytes interact with endothelial and epithelial cells through integrins [α4β7, α(E)β₇,  α₄β₁, α(L)β₇] and their ligands, adhesion molecules (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25, CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing.

The development of antiadhesion molecules in IBD is evolving into a very interesting therapeutic strategy. There are several approved and some investigational antibodies and small molecules including natalizumab (anti-α₄), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9). Some had safety concerns namely PML was a particular risk in natalizumab. It is hope that the newer gut specific anti-adhesion molecules will have an impact on both efficacy and safety in inflammatory bowel disease.

Current data seems to show that only selective blockade of α4β7 can induce clinical response and remission in IBD, while blocking MAdCAM or β7 integrin has little clinically effect. More large randomized controlled trials are needed especially for etrolizumab. Most current data shows anti-α4β7 agents may represent a valid alternative to biological systemic TNF inhibition, especially in anti-TNF non-responders. Similarly to anti-TNF agents, the direct blockade of integrins seems to be more effective than blocking integrin receptors.

Our group has been involved in randomized, placebo-controlled, double-blind trials of Vedolizumab for the induction and maintenance of clinical response & remission in patients with active Crohn’s disease and an open-label study to determine it’s long-term safety & efficacy in patients with ulcerative colitis & Crohn’s disease.

trials

The moderate success of the anti-integrin antibody Vedolizumab highlights that, to date, the biologic options in Crohn’s disease and ulcerative colitis have barely evolved beyond TNF blockers. This contrasts with other similar immune-related diseases, such as psoriasis and rheumatoid arthritis, where approved biologics target several independent biological mechanisms. Our group was involve in the clinical development of several agents proven ineffective, or less effective than originally anticipated. See the clinical trials list for studies currently recruiting.

1. Vercirnon.

This is an investigational non-biologic, orally administered CCR9 antagonist. This is a small molecule which specifically blocks the migration of gut-specific T cells which selectively home to the intestine. Its target is the G-protein coupled receptor CCR9 expressed by most T cells in the thymus as well as in the intestine and by a small population of T cells in the peripheral blood. Our group was part of a global randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of two doses (500 mg once daily and 500 mg twice daily) of vercirnon compared to placebo over 12 weeks in 608 adult patients with moderate-to-severe active Crohn’s disease. The patients were not adequately controlled with conventional therapy, and included patients who did not respond to tumor necrosis factor-alpha (TNF-α) antagonists. The study failed to achieve the primary and key secondary endpoints. Further studies are planned.

2. Ustekinumab

This multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of ustekinumab therapy in subjects with moderately to severely active Crohn’s disease previously treated with TNF antagonist therapy. The data  suggested the beneficial effect of IL-12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn’s disease patients who have previously failed on TNF blockers.

3. Certolizumab

Multinational, randomized, double-controlled trial to assess the efficacy and safety of certolizumab pegol, a pegylated Fab’fragment of a humanised anti-TNF-alpha monoclonal antibody, administered subcutaneously at weeks 0, 2 and 4 in subjects with moderately to severely active Crohn’s Disease.

4. Golumimab

Little was known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC) until the PURSUIT data.  Our group were investigators on these multicentre double-blind induction and maintenance trials for subcutaneous golimumab in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis.   Rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission were 17.8%, 17.9% and 6.4%  and mucosal healing 42.3%, 45.1% and 28.7% for both doses compared to placebo group (P ≤ .0014, all comparisons). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis. Safety was consistent with that reported for other TNFα antagonists.

What is the optimal approach for patients to prevent further disease after Crohn's disease surgery? Is early endoscopic monitoring important and can faecal calprotectin (FC) substitute for endoscopic monitoring? Is it possible to regain remission after endoscopic recurrence? Is ongoing monitoring needed after early remission?

Disease recurs in most Crohn’s disease patients after intestinal resection, with endoscopic recurrence preceding clinical recurrence. We investigated these above questions in this Australian  Post-Operative Crohn’s Endoscopic Recurrence (POCER) treat-to-target study of 174 paients. All patients received 3 months metronidazole. High risk patients (smoker, perforating disease, ≥2nd operation) also received daily thiopurine, or adalimumab if thiopurine intolerant. Patients were randomised 2:1 to colonoscopy at 6 months (122 pts in “active care”) or no colonoscopy ( 52 pts in “standard care”).  Endoscopic remission was defined as Rutgeerts score i0 or i1 and recurrence as ≥i2. For endoscopic recurrence at 6 months low risk patients stepped up to thiopurine, high risk patients stepped up to adalimumab fortnightly, and high risk thiopurine-intolerant patients stepped up to weekly adalimumab. 39% stepped up at  6 months. All patients had a colonoscopy at 18 months with primary end-point endoscopic recurrence at 18 months. FC, CRP and CDAI were measured pre-operatively, and at 6, 12, & 18 months. The data showed a statistically significant difference (P = 0.028) in 18 months endoscopic recurrence between active care (49%) v  standard care patients (67%).  Step up at 6 months brought 38% of patients with endoscopic recurrence into remission 1 year later; conversely endoscopic disease recurred 1 year later in 41% of patients who were in remission at 6 months.  Fecal calprotectin correlated with endoscopic recurrence (r = 0.42, p < 0.001) and score (r = 0.44, p < 0.001); CRP and CDAI did not.  FC >100mcg/g indicated endoscopic recurrence with a sensitivity 0.89 and NPV 91%, potentially allowing avoidance of colonoscopy in 41% of patients. The data from the study seems to show treating according to risk of recurrence, with early colonoscopy and selective treatment step-up for recurrence, is superior to optimal drug therapy alone in preventing post-op disease recurrence. Early endoscopic remission requires ongoing monitoring.  However, FC can be used to monitor for recurrence and is superior to CRP and CDAI.

Can we minimise adverse effects of corticosteroids in ulcerative colitis patients who need them?

Corticosteroids are effective in treating active UC, but due to their adverse effects, are usually reserved for selected patients. Budesonide, coupled with a colonic release system (MMX Multi-Matrix System) has demonstrated promising clinical efficacy in UC, while minimising systemic side effects. Our group was part of an international study to investigate the efficacy of once-daily budesonide MMX for the induction of combined clinical and endoscopic remission in patients with active, mild-to-moderate UC compared with placebo and an active control. Budesonide MMX 9 mg provided a statistically significant increase in the combined clinical and endoscopic remission rate compared with placebo (17.4% vs 4.5%; p=0.0047). Budesonide MMX 9 mg also improved the rates of histological healing and symptom resolution compared with placebo.  Colonic-release budesonide may be a useful alternative to conventional corticosteroid therapy for the treatment of active, mild-to-moderate UC.

What is a Clinical Trial?

Clinical Trial Studies are scheduled in Phases according to what question is being answered regarding a drug, test or treatment.

Phase 1

Phase 1 Clinical Trials study the safety of a new drug.  They usually involve few patients (20 – 80) and are focused on finding safe dosage of a drug and identifying side effects

Phase 2

Phase 2 Clinical Trials study whether a drug is Safe and Effective. Larger Number of Patients (100 – 300) are enrolled with the aim to identify short term side effects and efficacy.

Phase 3

Phase 3 (Phase III) Clinical Trials further evaluate whether a drug is Safe and Effective and Compare it to traditional treatments currently on the market. Larger Groups of Patients (1,000 – 3,000) are enrolled. The aim is to test safety and efficacy against a placebo or a current standard of care? Further data on side effects is collected.

Phase 4

Phase 4 (Phase IV) Clinical Trials study post-marketing Information about the Drug / Therapy. These trials compare treatment to Other Threrapies, Identify / Monitor Side Effects, Further Evaluate Safety and efficacy, assess risks and benefits and optimal use of the drug or therapy.

http://clinicaltrials.gov/ct2/about-studies/learn