Highlights in Crohn’s Disease and Ulcerative Colitis

Gastroenterology & Hepatology Volume 8, Issue 8, Supplement 5 August 2012

Digestive Disease Week 2012

May 19–22, 2012 • San Diego, California

Special Reporting on:

• Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active UC: PURSUIT-SC

• The Future of IBD Therapy: Individualized and Optimized Therapy and Novel Mechanisms

• Infliximab Concentration and Clinical Outcome in Patients with UC

• Vedolizumab Induction Therapy for UC: Results of GEMINI I, A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase III Trial

• Novel Infliximab and Antibody-to-Infliximab Assays Are Predictive of Disease Activity in Patients with CD

• Accelerated Step-Care Therapy with Early Azathioprine Versus Conventional Step-Care Therapy in CD

• PIANO: A 1,000-Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators and Biologic Therapy

PLUS Meeting Abstract Summaries

With Expert Commentary by:
William J. Sandborn, MD
Chief of the Division of Gastroenterology
Director of the UCSD IBD Center
UC San Diego Health System
La Jolla, California

A Phase II/III Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active Ulcerative Colitis: PURSUIT-SC

Over the past several years, the role of tumor necrosis factor-α (TNF-α) in the pathogenesis of ulcerative colitis (UC) has become more firmly established, with a wide variety of data from both preclinical and clinical settings providing evidence of its importance in the disease process. Based on this knowledge, numerous agents that inhibit TNF-α have been tested for the treatment of UC, and some of these agents have gained approval from the US Food and Drug Administration (FDA).

One new anti–TNF-α agent, golimumab, is different from other monoclonal anti–TNF-α antibodies in that it targets a unique epitope on the TNF-α molecule. Preclinical studies have demonstrated that golimumab binds with high affinity to both the soluble and membrane-bound forms of TNF-α.¹ Further, studies have shown that golimumab is superior to other anti–TNF-α antibodies in terms of its ability to inhibit both TNF-α–mediated cytotoxicity and TNF-α–mediated endothelial cell activation.

A human monoclonal antibody directed against TNF-α, golimumab is currently approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis—all conditions in which TNF-α has been implicated—and golimumab is currently being evaluated as a possible treatment for UC. At the 2012 Digestive Disease Week (DDW) meeting, held May 19–22, 2012 in San Diego, California, William Sandborn presented results of the PURSUIT-SC study, a clinical trial that evaluated the safety and efficacy of golimumab as induction therapy for the treatment of moderate-to-severe UC.²

PURSUIT-SC was a randomized, placebo-controlled, double-blind, phase II/III trial that enrolled UC patients who were naïve to anti–TNF-α therapy. Enrolled patients had moderately to severely active UC (as defined by a Mayo Clinic score of 6–12 with an endoscopy subscore of 2 or 3) and were either receiving adequate treatment (including 6-mercaptopurine, azathioprine, corticosteroids, and/or 5-aminosalicylic acid), had previously failed to respond to or tolerate treatment with these agents, or were corticosteroid-dependent.

The design of the PURSUIT-SC trial was unique in that it began as a phase II dose-ranging study, after which patients were integrated into the confirmatory phase III portion of the study. During the dose-ranging portion of the study, patients were randomized to 1 of 4 arms: placebo, 100/50 mg golimumab (100 mg at Week 0 and 50 mg at Week 2), 200/100 mg golimumab (200 mg at Week 0 and 100 mg at Week 2), or 400/200 mg golimumab (400 mg at Week 0 and 200 mg at Week 2). During the phase III portion of the study, only the 200/100 mg and 400/200 mg doses of golimumab were used. Golimumab was administered subcutaneously in all groups.

The primary endpoint of the study was clinical response at Week 6, which was defined as a decrease in the Mayo Clinic score of at least 30% and at least 3 points from baseline, with either a decrease in the rectal bleeding subscore of at least 1 point from baseline or a rectal bleeding subscore of 0 or 1. Secondary endpoints included clinical remission (defined as a Mayo Clinic score ≤2 with no individual subscore >1), mucosal healing (defined as a Mayo Clinic endoscopy subscore of 0 or 1), and change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) score, all assessed at Week 6.

A significantly higher proportion of patients in the golimumab treatment groups attained the primary endpoint of clinical response at Week 6 compared to the placebo group (51.8% and 55.0% in the 200/100 mg
golimumab and 400/200 mg golimumab arms, respectively, vs 29.7% in the placebo arm; P<.0001 for both comparisons vs placebo). A highly significant difference also emerged in terms of the proportion of patients who achieved clinical remission at Week 6 (6.3% in the placebo group vs 18.7% in the 200/100 mg golimumab group and 17.8% in the 400/200 mg golimumab group; P<.0001 for both comparisons vs placebo) and mucosal healing at Week 6 (28.5% in the placebo group vs 43.2% in the 200/100 mg
golimumab group and 45.3% in the 400/200 mg golimumab group; P=.0005 and P<.0001, respectively). The mean change from baseline in IBDQ scores at Week 6 was 14.6 points in the control group versus 27.4 points in the 200/100 mg golimumab group and 27.0 points in the 400/200 mg golimumab group (P<.0001 for both comparisons vs placebo).

The PURSUIT-SC study also evaluated the overall phase II/III trial population through Week 6 to assess the safety profile of golimumab; this analysis included a total of 1,065 patients.
The total proportion of patients who experienced an adverse event was 38.2% in the placebo group versus 39.1% for the combined golimumab group. The number of patients who experienced a serious adverse event was also relatively similar in both groups (6.1% in the placebo group vs 3.0% in the combined golimumab group). Rates of adverse events and serious adverse events were similar between the 200/100 mg golimumab and 400/200 mg golimumab groups. Malignancies were rare in all groups, occurring at rates of 0.3%, 0%, and 0.3% in the placebo, 200/100 mg golimumab, and 400/200 mg golimumab groups, respectively. Injection site reactions were also rare and occurred at similar rates across golimumab dosage groups. One patient in the 400/200 mg golimumab arm died, and demyelination (a well-described toxicity of anti–TNF-α therapy) was reported in 1 patient in the 400/200 mg golimumab arm.

In conclusion, the PURSUIT-SC study showed that golimumab produced clinical response and remission by
Week 6, induced mucosal healing, and improved health-related quality of life. Further, the safety profile of golimumab when used for the treatment of UC proved relatively similar to the safety profile observed when golimumab is used for the treatment of rheumatologic conditions, as well as the safety profile observed with other anti–TNF-α drugs.

References

1. Shealy D, Cai A, Staquet K, et al. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor alpha. MAbs. 2010;2:428-439.

2. Sandborn W, Feagan B, Marano C, et al. A phase 2/3 randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of subcutaneous golimumab induction therapy in patients with moderately to severely active ulcerative colitis: PURSUIT-SC. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract L6100.

The Future of IBD Therapy: Individualized and Optimized Therapy and Novel Mechanisms

In a Presidential Plenary lecture at the 2012 DDW meeting, William Sandborn summarized several recent advances in the treatment of inflammatory bowel disease (IBD). Many of these advances relate to individualized therapeutic strategies for patients with UC and Crohn’s disease (CD).

Customized Drug Dosing

One of the major trends that will define the future of IBD therapy is the increased use of pharmacokinetics to customize drug dosing for individual patients. Monoclonal antibody therapeutics are especially susceptible to factors that affect their pharmacokinetic characteristics.¹ For example, the presence of antidrug antibodies (ADAs) decreases the serum concentration of therapeutic monoclonal antibodies and can cause a 3-fold increase in the clearance of the therapeutic antibody. Notably, clinical studies of IBD patients treated with monoclonal antibodies demonstrate that patients with detectable ADAs have worse clinical outcomes than patients who do not develop ADAs.

Another factor that affects the pharmacokinetic characteristics of monoclonal antibodies is the concomitant use of immunosuppressant therapy, which has been shown to reduce formation of ADAs, increase the serum concentration of the therapeutic monoclonal antibody, and decrease its clearance. IBD patients who are receiving monoclonal antibody therapies plus concomitant immunosuppressant therapy often have improved clinical outcomes compared to patients who receive the antibody alone.

Finally, increased clearance of therapeutic monoclonal antibodies—which results in decreased serum concentrations of the antibody—has been associated with high baseline serum concentration of TNF-α, low serum albumin levels, and high baseline levels of the inflammatory marker C-reactive protein (CRP). Certain patient-related factors have also been shown to impact the pharmacokinetics of therapeutic monoclonal antibodies, including high body mass index and male sex, both of which may increase clearance.

The relationship between serum concentrations of the therapeutic monoclonal antibody and clinical outcomes was recently demonstrated in an analysis of the ACT-1 and ACT-2 studies.² In this analysis, patients from these 2 trials were pooled and divided into quartiles according to serum infliximab concentrations; the proportion of patients with a clinical response at Week 8 was found to increase with increasing serum concentration of infliximab. Only 33.2% of placebo-treated patients achieved a clinical response at Week 8 compared to 52.6%, 69.0%, 75.4%, and 81.0% of patients in the 1st, 2nd, 3rd, and 4th infliximab serum concentration quartiles, respectively. Similarly, 13.1% of placebo-treated patients achieved clinical remission at Week 30 compared to 14.6%, 25.5%, 59.6%, and 52.1% of patients in the 1st, 2nd, 3rd, and 4th infliximab serum concentration quartiles, respectively.

New Treatment Endpoints

Another important trend in treatment for IBD is the evolution of treatment endpoints from resolution of symptoms to mucosal healing, prevention of structural damage, and prevention of disability. Colombel and colleagues recently demonstrated an association between mucosal healing at Week 8 and time to colectomy among infliximab-treated patients.³ Significantly fewer patients with a Mayo Clinic endoscopy subscore of 0 or 1 required colectomy or commercial infliximab use compared to patients with an endoscopy subscore of 2 or 3 (P<.0001). This same study showed a significant association between Mayo Clinic endoscopy subscore at Week 8 and corticosteroid-free symptomatic remission at Week 30 during treatment with anti–TNF-α antibody therapy (P<.001). The rate of Week 30 corticosteroid-free symptomatic remission was 46% among patients with a Mayo Clinic endoscopy subscore of 0 at Week 8 versus 34%, 11%, and 6.5% for patients with endoscopy subscores of 1, 2, and 3, respectively.

By using deep remission as a treatment endpoint for CD, clinicians are aiming to manage the patient’s disease in a way that addresses the underlying disease process, rather than just controlling symptoms. For patients with no bowel damage or disability, the goal of achieving deep remission is to prevent damage and disability; in these patients, deep remission is defined as resolution of 1 or more objective measures of inflammation (monitored via endoscopy, biomarkers, or imaging) and resolution of symptoms. For patients who already have existing bowel damage or disability, the goal of achieving deep remission is to prevent further damage and disability and to reverse damage, if possible; in this group, the definition of deep remission is the resolution of 1 or more objective measures of inflammation (monitored via endoscopy, biomarkers, or imaging) and improvement of symptoms, if possible.

The importance of achieving deep remission was demonstrated in an analysis of the EXTEND trial.^4,5 In this study, deep remission was defined as clinical remission (Crohn’s Disease Activity Index [CDAI] score <150 points) and complete mucosal healing. None of the 11 patients who achieved deep remission with adalimumab at Week 12 required hospitalization through Week 52; in comparison, the rate of all-cause hospitalization among patients who did not achieve deep remission at Week 12 was 17% (9 of 53 patients). The same trend was observed for CD-related hospitalization through Week 52, which occurred in 0% and 9% of patients with and without deep remission, respectively.

A number of measures have now been developed to help clinicians assess the extent of bowel damage and disability. Pariente and colleagues recently published a newly developed CD Digestive Damage Score, called the Lémann score, which can be used to map a patient’s disease course on a double-axis graph.⁶ In this graph, time is shown on the x-axis, digestive damage is on the left y-axis, and inflammatory activity is on the right y-axis; the slope of the line connecting the data points gives a measure of disease progression. Further, Peyrin-Biroulet and colleagues recently reported the development of the first disability index for IBD, which is based on the international classification of functioning, disability, and health.⁷ A total of 19 core set categories were used to develop the index: 7 for body functions, 2 for body structures, 5 for activities and participation, and 5 for environmental factors.

Combination Therapy and New Agents

Another important trend in the treatment of IBD is the shift from single-agent azathioprine therapy to combination therapy. Data from Sans and colleagues showed that the early use of azathioprine in patients with recently diagnosed CD can have a corticosteroid-sparing effect.⁸ Further, the SONIC trial demonstrated the safety and efficacy of infliximab and azathioprine given prior to immunosuppressive or biologic therapy; this trial randomized 508 CD patients with moderate-to-severe disease to single-agent azathioprine therapy, infliximab monotherapy, or combination therapy with both drugs.⁹ The SONIC trial was the first study to conclusively show that infliximab monotherapy yielded higher rates of corticosteroid-free clinical remission (assessed at Week 26) than single-agent azathioprine therapy (44.4% vs 30%; P=.009). SONIC also showed that these rates could be further increased when infliximab and azathioprine were used in combination (56.8%; P=.022 for combination therapy vs infliximab monotherapy; P<.001 for combination therapy vs single-agent azathioprine therapy).

Finally, several advances in the treatment of IBD are related to the discovery of novel biologic targets. One such target is the α4β7 integrin, which is targeted by the gut-specific humanized monoclonal antibody vedolizumab (MLN0002). This drug has unique pharmacologic properties that confer specificity and selectivity for treatment of IBD, and previous phase II trials have demonstrated that vedolizumab is active for the treatment of both CD and UC.^10-12

Building on these studies, a phase III study of vedolizumab was recently conducted, and the results of this study were reported by Brian Feagan during the 2012 DDW meeting.¹³ This study was a randomized, placebo-controlled, double-blind, multicenter, phase III trial that assessed the activity of vedolizumab in patients with treatment-refractory, moderately to severely active UC. A total of 374 patients were enrolled in this study; patients had a mean age of 40.5 years and a mean disease duration of 6.5 years. Patients were randomized to receive either
300 mg intravenous vedolizumab or placebo on Days 1 and 15.

All 3 of the efficacy endpoints assessed at Week 6 revealed significant improvements among patients treated with vedolizumab compared to patients who received placebo. Rates of clinical response were 47.1% for vedolizumab versus 25.5% for placebo (P<.001), rates of clinical remission were 16.9% and 5.4%, respectively (P=.0009), and rates of mucosal healing were 40.9% and 24.8%, respectively (P=.0012). Among patients who had previously received treatment with an anti–TNF-α agent, rates of clinical response were 39% for vedolizumab-treated patients versus 20.6% for the placebo group; these rates increased to 53.1% and 26.3%, respectively, among patients who were naïve to anti–TNF-α agents.

Another target under active investigation for the treatment of IBD is interleukin (IL) 12/23p40, which is targeted by the humanized monoclonal antibody ustekinumab. This antibody binds specifically to the p40 protein subunit that is shared by both IL-12 and IL-23, 2 cytokines whose immune system activity has been implicated in the pathogenesis of CD and other autoimmune disorders.¹⁴

In a study presented at DDW 2011, ustekinumab was evaluated in 526 CD patients who were randomized to receive either placebo or 1 of 3 doses of ustekinumab (1 mg/kg, 3 mg/kg, or 6 mg/kg) given as a single intravenous infusion.¹⁵ All patients had active disease and were resistant to or intolerant of previous anti–TNF-α therapy. This study found that significantly more ustekinumab-treated individuals achieved a clinical response at Week 6 compared to patients who received placebo (36.8% vs 23.5%; P=.005). These differences remained significant across dosage groups, with clinical response at Week 6 being achieved by 36.6% of patients in the 1 mg/kg ustekinumab group (P=.021), 34.1% of patients in the 3 mg/kg ustekinumab group (P=.057), and 39.7% of patients in the 6 mg/kg ustekinumab group (P=.005; all comparisons vs placebo). After the initial ustekinumab infusion, patients were re-randomized to receive either placebo or 90 mg subcutaneous ustekinumab at Weeks 8 and 16. Early in therapy, the rate of clinical remission did not show a significant difference between placebo and ustekinumab; however, this difference became greater with continued ustekinumab treatment. The rate of clinical remission at Week 22 was 41.7% with ustekinumab versus 27.4% with placebo (P=.029).

A third target being pursued for treatment of IBD is the Janus kinase (JAK). Acting via JAK inhibition, the new drug tofacitinib modulates signaling of several proinflammatory cytokines. Tofacitinib was recently evaluated in a multicenter, double-blind, phase II, clinical trial that used model-fitted clinical response rates at Week 8 as its primary efficacy endpoint.¹⁶ A total of 194 patients with moderate-to-severe UC, a Mayo Clinic score of 6 or higher, and an endoscopy subscore of 2 or higher were enrolled in this study; patients were randomized to placebo or 1 of 4 doses of tofacitinib (0.5 mg, 3 mg, 10 mg, or 15 mg) twice daily for 8 weeks. The estimated clinical response rate with placebo was 38.1%; this rate increased steadily with increasing dosage of tofacitinib, with response rates of 39.4%, 46.1%, 65.0%, and 76.3% among patients in the 0.5 mg, 3 mg, 10 mg, and 15 mg tofacitinib groups, respectively. At a dose of 10 mg twice daily, tofacitinib resulted in a 26.9% increase over placebo in the estimated clinical response rate at Week 8 (90% confidence interval [CI], 17.0–36.8); at 15 mg twice daily, a 38.2% increase over placebo was observed (90% CI, 25.3–51.2).

References

1. Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635-646.

2. Reinisch W, Feagan BG, Rutgeerts PJ, et al. Infliximab concentration and clinical outcome in patients with ulcerative colitis. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 566.

3. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141:1194-1201.

4. Colombel JF, Rutgeerts P, Sandborn WJ. Deep remission for adalimumab-treated patients with moderate to severe ileocolonic Crohn’s disease: results from EXTEND. J Crohns Colitis. 2010;4:S10.

5. Colombel JF, Rutgeerts P, Sandborn WJ. Deep remission predicts long-term outcomes for adalimumab-treated patients with Crohn’s disease: data from EXTEND. Gut. 2010;59(suppl 3):A80.

6. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17:1415-1422.

7. Peyrin-Biroulet L, Cieza A, Sandborn WJ, et al. Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health. Gut. 2012;61:241-247.

8. Sans M, López-San Román A, Esteve M, et al. Early use of azathioprine has a steroid sparing effect on recently diagnosed Crohn’s disease patients. Gastroenterology. 2011;140(5 suppl 1):S-109.

9. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383-1395.

10. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-875.

11. Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. 2012;18:1470-1479.

12. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008;6:1370-1377.

13. Feagan BG, Rutgeerts PJ, Sands BE, et al. Vedolizumab induction therapy for ulcerative colitis: results of Gemini 1, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943b.

14. Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011;3:535-545.

15. Sandborn WJ, Gasink C, Gao L-L, et al. A multicenter, randomized, double-blind, placebo-controlled phase2b study of ustekinumab, a human monoclonal antibody to IL-12/23p40, in patients with moderately to severely active Crohn’s disease: results through Week 22 from the Certifi trial. Presented at Digestive Disease Week; May 7–10, 2011; Chicago, Illinois. Abstract 592.

16. Sandborn WJ, Ghosh S, Panes J, et al. Phase 2 study of CP-690,550, an oral janus kinase inhibitor, in active ulcerative colitis. Presented at Digestive Disease Week; May 7–10, 2011; Chicago, Illinois. Abstract 594.

ABSTRACT SUMMARY Efficacy and Safety of Budesonide MMX 6 mg for the Maintenance of Remission in Patients with Ulcerative Colitis: Results From a Phase III, 12-Month Safety and Extended-Use Study

Two studies presented at the DDW 2012 meeting examined budesonide MMX, a novel formulation of the nonsystemic corticosteroid budesonide that is designed to deliver active drug to the colon.^1,2 A 12-month, placebo-controlled, phase III, extended-use study was conducted to evaluate the efficacy and safety of budesonide MMX for maintenance of remission in patients with UC. Patients received induction therapy with 9 mg budesonide MMX in either a phase III induction trial or an open-label study, after which 122 patients who were in clinical and endoscopic remission were randomized to

12 months of maintenance treatment with either placebo or 6 mg budesonide MMX once daily. Clinical remission following induction therapy was defined according to the following criteria: UC Disease Activity Index (UCDAI) score no greater than 1 point after 8 weeks, no rectal bleeding, normal stool frequency, no mucosal friability at full colonoscopy, and a greater-than-1-point reduction from baseline in endoscopic score. Maintenance of remission during this extended study was defined as UCDAI subscores of 0 for both rectal bleeding and stool frequency.

While this trial was not powered to show statistical significance, an exploratory evaluation determined the proportion of patients who were in clinical remission after 1, 3, 6, 9, and 12 months (and/or the end of study/early withdrawal visit). A safety analysis was also conducted at each of these time points. In addition, time to clinical relapse was assessed as a secondary endpoint; this endpoint was defined as the time in days until the recurrence of rectal bleeding or stool frequencies at least 1–2 stools/day greater than normal for the patient.

In one poster presented at the 2012 DDW meeting, William Sandborn and colleagues presented efficacy results of this study.¹ This analysis demonstrated that the proportion of patients who maintained remission with budesonide MMX was not significantly different than the proportion of patients who maintained remission with placebo. This lack of difference was potentially due to insufficient statistical power. However, the probability of clinical relapse at 12 months was significantly decreased in the budesonide MMX arm compared to the placebo arm (intent-to-treat population, 40.9% vs 59.7%, respectively; P=.0224). Additionally, analysis of the intent-to-treat population showed that the median time to clinical relapse was significantly prolonged with budesonide MMX versus placebo (log-rank test P=.0224).

Safety results from this phase III trial were presented by Simon Travis and colleagues in a separate poster.² This safety analysis included data from 123 patients. The rate of treatment-related adverse events was similar between the budesonide MMX arm and the placebo arm (21.0% vs 21.3%, respectively). The most frequent adverse events were ulcerative colitis, osteopenia, Cushing syndrome, abdominal pain, flushing, and hirsutism. Only 1 patient in each arm reported a serious adverse event, neither of which were related to the study drug. There were no deaths or life-threatening events during the study. Finally, the overall incidence of potential glucocorticoid effects was similar between budesonide MMX–treated patients and placebo-treated patients (14.5% vs 11.5%, respectively); these side effects included moon face, striae rubrae, flushing, fluid retention, mood and sleep changes, insomnia, acne, and hirsutism.

References

1. Sandborn WJ, Danese S, Ballard ED, et al. Efficacy of budesonide MMx 6 mg QD for the maintenance of remission in patients with ulcerative colitis: results from a phase III, 12 month safety and extended use study. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Su2080.

2. Travis S, Danese S, Ballard ED, et al. Safety analysis of budesonide MMx 6 mg used for the maintenance of remission in patients with ulcerative colitis: results from a phase III, 12 month safety and extended use study. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Su2088.

Infliximab Concentration and Clinical Outcome in Patients with Ulcerative Colitis

The ACT-1 and ACT-2 studies were multicenter, randomized, double-blind, placebo-controlled trials that compared 5 mg/kg and 10 mg/kg doses of infliximab versus placebo for the treatment of moderate-to-severe UC.¹ Each study enrolled 364 patients between March 2002 and March 2005, and all patients had a Mayo Clinic score of 6–12 points. Treatment was administered at Weeks 0, 2, and 6, followed by maintenance therapy every 8 weeks through Week 22 in ACT-2 and through Week 46 in ACT-1. The primary study endpoint was clinical response at Week 8; secondary endpoints included clinical response or remission with discontinuation of corticosteroids at Week 30 in both studies (and at Week 54 in ACT-1), clinical remission and mucosal healing at Weeks 8 and 30 in both studies (and at Week 54 in ACT-1), and clinical response at Week 8 in patients with steroid-refractory disease. In both studies, clinical response was defined as a decrease in the Mayo Clinic score of at least 3 points and at least 30%, with an accompanying decrease of at least 1 point in the rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1.

Significantly more patients in both the 5 mg/kg and 10 mg/kg infliximab groups achieved clinical response at Week 8 compared to patients in the placebo arm (69% and 62% vs 37%; P<.001 for both comparisons vs placebo). In both trials, infliximab-treated patients were more likely to achieve clinical response at Week 30 (P≤.002 for all comparisons). ACT-1, which had a longer follow-up period, also showed that more of the patients treated with infliximab (either 5 mg/kg or 10 mg/kg) achieved a clinical response at Week 54 (46% and 44%, respectively) compared to patients who received placebo (20%; P<.001 for both comparisons).

Building on this research, a post–hoc analysis of the ACT-1 and ACT-2 studies was conducted to evaluate the association between serum infliximab concentrations and clinical outcomes in patients with moderately to severely active UC; Walter Reinisch presented results of this post–hoc analysis during the 2012 DDW meeting.² While the ACT studies examined 2 doses of infliximab, the post–hoc analysis only evaluated patients in the 5 mg/kg infliximab dosage group, as this is the dose that was approved by the FDA as a treatment for UC.

Pharmacokinetic sampling was performed throughout the ACT-1 and ACT-2 studies, most often at the time of an infusion, although samples were also taken at Week 8. By Week 8, the subset of UC patients who were responding to infliximab began to diverge from the group of patients who did not respond to infliximab. Interestingly, there was no significant difference in peak serum infliximab levels between the responding and nonresponding patients at this time point. In contrast, trough infliximab levels were lower in nonresponding patients versus responding patients.

Further analysis demonstrated that patients who achieved a clinical response at Week 8 had a serum infliximab concentration of 35 µg/mL, compared to a serum infliximab concentration of 25.8 µg/mL in patients who did not achieve a clinical response; this difference was statistically significant. Similarly, patients who achieved and did not achieve mucosal healing by Week 8 had serum infliximab concentrations of 36.1 µg/mL and 26 µg/mL, respectively; this difference did not achieve statistical significance.

At Week 30, trough infliximab concentrations were again higher among patients who achieved a clinical response compared to those who did not (5 µg/mL vs 1.2 µg/mL). Interestingly, there was a large amount of variability in serum infliximab concentrations between responders and nonresponders and between patients who achieved mucosal healing and those who did not. At the time of the Week 30 trough level measurement, this separation increased further. This finding could be attributed to the increased rate of drug clearance due to development of immunogenicity. When serum infliximab concentrations were divided into quartiles, Reinisch and colleagues found that there was an incremental increase in the likelihood of achieving clinical response or mucosal healing with each higher quartile of infliximab concentration; the same trends were shown for clinical remission at Weeks 30 and 54.

From this post–hoc analysis, the investigators concluded that serum infliximab concentrations began to diverge as early as Week 8 between patients who achieved an endpoint (either clinical response or mucosal healing) and those who did not. While the serum infliximab concentrations required to achieve response and maintain remission varied substantially among patients, higher serum infliximab concentrations were associated with a greater likelihood of achieving these endpoints. The investigators acknowledged that a prospective study is needed to determine whether adjustment of serum infliximab concentrations has clinical utility for optimizing patient outcomes.

References

1. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462-2476.

ABSTRACT SUMMARY The Prevalence of Human Antichimeric Antibodies in Patients on Infliximab Increases with Age

In another poster presented at the 2012 DDW meeting, David Barry and Richard S. Bloomfeld reported on a study in which they determined the prevalence of human antichimeric antibodies among infliximab-treated IBD patients and correlated the presence of these antibodies with patient age.¹ In this retrospective analysis, all human antichimeric antibody testing performed by Prometheus Laboratories between November 2000 and January 2011 was evaluated. A total of 26,450 patients were included in this analysis; individuals younger than 10 years and older than 80 years of age were excluded. Patients were divided into 7 age groups, with each group spanning a range of 10 years. A negative human antichimeric antibody result was defined as a serum concentration below 1.69 μg/mL, while a positive result was defined as a serum concentration above 1.69 μg/mL.

The proportion of patients with a negative human antichimeric antibody result decreased significantly with increasing patient age (Chi square; P<.0001). Of the 10,155 patients aged 10–19 years, 81.9% had a negative human antichimeric antibody result. This percentage decreased to 80% of 4,004 patients aged 20–29 years, 78.9% of 3,831 patients aged 30–39 years, 79.9% of 3,509 patients aged 40–49 years, and 79.9% of 2,735 patients aged 50–59 years. This number continued to decrease in older patients, with 77.8% of patients aged 60–69 years and 74.8% of patients aged 70–79 years having a negative human antichimeric antibody result.

Based on these data, the investigators concluded that human antichimeric antibodies increase in prevalence among older infliximab-treated IBD patients. This finding could have a significant impact on clinical decision-making in young versus older IBD patients who lose response to anti–TNF-α therapy.

Reference

1. Barry D, Bloomfeld RS. The prevalence of human antichimeric antibodies in patients on infliximab increases with age. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Sa2040.

Vedolizumab Induction Therapy for Ulcerative Colitis: Results of GEMINI I, A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase III Trial

Given the limitations of current therapies for UC, novel therapeutic strategies with new mechanisms of action are needed. One such agent is vedolizumab, a novel, gut-selective, monoclonal antibody directed against the α4β7 integrin, which induces selective inhibition of lymphocytic trafficking in the gut. This selective inhibition offers a possible advantage over the more systemic effects elicited by natalizumab, which inhibits both the α4β1 and α4β7 integrins.

At the 2012 DDW meeting, Brian Feagan presented the results of a randomized, placebo-controlled, double-blind, multicenter, phase III trial designed to determine the long-term efficacy and safety of vedolizumab when given as induction therapy for UC.¹ All patients in this study had moderately to severely active UC and had failed at least 1 prior therapy. The intent-to-treat population for the induction phase of this study consisted of 374 patients with active UC. All patients had a Mayo Clinic score of 6 or higher and an endoscopy subscore of 2 or higher despite treatment with corticosteroids, purine antimetabolites, and/or anti–TNF-α agents. Patients were randomized 3:2 to treatment with vedolizumab or placebo; vedolizumab was administered as a 300-mg intravenous dose on Days 1 and 15.

The primary study endpoint for the induction phase of the study was clinical response at Week 6; clinical response was defined as a reduction in the total Mayo Clinic score of at least 3 points and a decrease from baseline of at least 30% plus a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore no greater than 1. Secondary endpoints for the induction phase of the study included mucosal healing and clinical remission. Clinical remission was defined as a total Mayo Clinic score no greater than 2 points with no individual subscore greater than 1; mucosal healing was defined as a Mayo Clinic endoscopy subscore no greater than 1. The mean age of patients in this study was 40.5 years, the mean disease duration was 6.5 years, and the mean baseline Mayo Clinic score (prior to the start of the induction phase) was 8.6 points.

The rate of clinical response at Week 6 was significantly higher in the vedolizumab arm compared to the placebo arm (47.1% vs 25.5%; P<.0001). Vedolizumab also showed significantly higher rates of clinical remission at Week 6 (16.9% for vedolizumab vs 5.4% for placebo; P=.0010) and mucosal healing at Week 6 (40.9% for vedolizumab vs 24.8% for placebo; P=.0013). Interestingly, the magnitude of improvement in clinical response was more profound among patients without prior anti–TNF-α exposure (26.8% improvement with vedolizumab vs placebo) compared to patients who had previously been exposed to anti–TNF-α agents (18.4% improvement with vedolizumab vs placebo). The same observation was found regarding the magnitude of improvement in clinical remission: 16.5% improvement for vedolizumab versus placebo in anti–TNF-α–naïve patients compared to 6.6% improvement for vedolizumab versus placebo in anti–TNF-α–experienced patients. Finally, preliminary analyses of the safety data through Week 6 showed similar rates of adverse events, serious adverse events, and serious infections for the vedolizumab group and the placebo group.

In conclusion, this trial demonstrated that vedolizumab is significantly more effective than placebo for induction of clinical response, clinical remission, and mucosal healing in patients with moderately to severely active UC, including patients who were previously exposed to anti–TNF-α therapy and those naïve to anti–TNF-α therapy.

Reference

1. Feagan BG, Rutgeerts PJ, Sands BE, et al. Vedolizumab induction therapy for ulcerative colitis: results of Gemini I, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943b.

Novel Infliximab and Antibody-to-Infliximab Assays Are Predictive of Disease Activity in Patients with Crohn’s Disease

Several theories have been proposed to explain why CD patients lose response to infliximab; low trough infliximab levels and the development of antibodies to infliximab (ATIs) are 2 of the most widely studied hypotheses. In 1 study of infliximab-treated CD patients, those with a loss of response had significantly lower infliximab trough levels (median,

0 µg/mL) and significantly higher ATI levels (median, 35 U/mL) compared to patients who maintained response (median infliximab level, 2.8 µg/mL; median ATI level, 0 U/mL; P<.0001 for both comparisons).¹ A separate study of 105 CD patients showed that ATIs were detectable in 21% of patients after a median of 14 infusions. Further, the rate of clinical remission with infliximab treatment was higher among individuals with detectable versus undetectable trough serum infliximab levels (82% vs 6%; P<.001). Detectable trough serum infliximab levels were also significantly associated with lower CRP levels (2 µg/L vs 11.8 µg/L; P<.001).² Thus, monitoring both infliximab trough levels and ATI levels may help to guide infliximab dose adjustment and clinical decision-making in order to optimize patient outcomes.

Several methods are available to measure infliximab trough and ATI levels. These methods include solid-phase enzyme-linked immunosorbent assay (ELISA), bridging ELISA, and radioimmunoassay. However, the utility of these assays is limited by their inability to accurately measure ATI levels in the presence of infliximab. At the 2012 DDW meeting, Severine Vermeire presented results showing that a novel homogeneous mobility shift assay can measure both ATI levels and infliximab trough levels without interference between the drug and
the antibody.³

This assay uses a fluorescently labeled version of infliximab, which is incubated in serum from an infliximab-treated CD patient. During this incubation period, the labeled infliximab complexes with any ATIs present in the sample. Following equilibration, both the labeled infliximab and the ATI-bound labeled infliximab complex are resolved by size-exclusion high-performance liquid chromatography (HPLC), with the latter complex displaying a later peak due to its larger size. The ratio of these 2 unique peaks results in the mobility shift.

This mobility shift assay was used to evaluate the association between infliximab trough levels, ATI levels, and disease activity (as assessed by CRP levels) in infliximab-treated CD patients. A total of 1,487 serum samples from 483 CD patients were analyzed; all patients had received maintenance infliximab therapy during 1 of 4 studies: (1) the COMMIT trial, a randomized controlled trial designed to evaluate the effect of an immunomodulator on maintenance infliximab therapy; (2) a cross-sectional Canadian study that investigated the loss of response to infliximab; (3) a cohort trial that assessed the effect of infliximab dosing on ATIs; and (4) a second cohort trial that studied the withdrawal of concomitant immunomodulator therapy in patients treated with infliximab and an immunomodulator. All serum samples were obtained while the patients were on maintenance treatment. Approximately two thirds (64%) of patients had infliximab trough levels of 3 µg/mL or higher,
and nearly one quarter (24%) of patients were ATI-positive. Because patients were on maintenance infliximab treatment, their disease was relatively well controlled; the median CRP level was 3.56 µg/L.

Using the mobility shift assay, both infliximab trough levels and ATI levels were measured. The majority of samples (72%) had high infliximab trough levels and no detectable ATIs. In contrast, only a small minority of samples (3.7%) had undetectable trough infliximab levels and no detectable ATIs. The remaining patients either had undetectable trough levels and detectable levels of ATIs (13.4%), or they had detectable infliximab trough levels and detectable ATI levels (10%). These data were used to construct a receiver operating characteristic curve, which showed that an infliximab cutoff of 3 µg/mL could accurately predict CD activity as measured by CRP level.

Among ATI-negative patients, the median CRP level was significantly lower in those individuals who had high infliximab trough levels. However, this inverse correlation was lost among ATI-positive patients, who showed high median CRP levels regardless of infliximab trough level. Multivariate analysis confirmed that both infliximab trough level and ATI status could independently predict CRP level. Infliximab trough levels negatively correlated with CRP levels, with the median CRP level being 52% lower in patients with an infliximab trough level of 3 µg/mL or higher compared to patients with an infliximab trough level below 3 µg/mL. ATI levels also correlated with CRP levels: In patients with an infliximab trough level below 3 µg/mL, the median CRP level was higher among ATI-positive patients compared to ATI-negative patients (8.4 µg/L vs 5.65 µg/L, respectively; P<.001). The same trend was observed in patients with an infliximab trough level of 3 µg/mL or higher (9.9 µg/L for ATI-positive patients vs 1.5 µg/L for ATI-negative patients; P<.01).

Based on these results, the investigators concluded that this novel homogeneous mobility shift assay could accurately measure both infliximab trough levels and ATI levels without the interference that limits other currently used assays. Using the homogeneous mobility shift assay, they confirmed that CRP levels were strongly associated with infliximab trough levels. Further, this study was the first to demonstrate that CRP levels were higher among ATI-positive patients versus ATI-negative patients independent of infliximab trough levels; this finding contradicts the previously held theory that ATI positivity would not predict high CRP levels as long as infliximab trough levels remained sufficiently high. Further study is required to determine the best strategy for management of patients who lose response to infliximab
and/or develop ATIs in the setting of sufficiently high trough infliximab levels.

References

1. Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Ainsworth MA. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46:310-318.

2. Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248-1254.

3. Feagan BG, Singh S, Lockton S, et al. Novel infliximab (IFX) and antibody-to-infliximab (ATI) assays are predictive of disease activity in patients with Crohn’s disease (CD). Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 565.

ABSTRACT SUMMARY New Assay to Detect Infliximab Levels and Anti-Infliximab Antibodies From a Single Serum Sample Is Useful in Measuring Efficacy of Treatment with Infliximab in Children with IBD

The most widespread method for detection of ATIs is a double-antigen ELISA, which uses infliximab as both the ligand and the detection antibody. However, this assay is limited by its inability to accurately determine ATI levels in the presence of serum infliximab concentrations. In a poster presented at the 2012 DDW meeting, Gabor Veres and colleagues reported on the development of a novel homogeneous mobility shift assay and demonstrated that it could detect both infliximab and ATIs in the same serum sample.¹

The homogeneous mobility shift assay uses fluorescently labeled infliximab, which has a molecular weight of approximately 150 kD. This labeled infliximab is incubated in serum from infliximab-treated patients, and the labeled infliximab forms complexes with any ATIs that may be present in the sample. The large fluorescently labeled infliximab-ATI complex has a distinct peak when subjected to HPLC. Similarly, fluorescently labeled TNF-α is also added to infliximab-treated serum; after incubation, this labeled TNF-α will be bound to any infliximab present in the sample. Again, the resulting immunocomplex has a high molecular weight and a distinctive peak by HPLC.

This novel homogeneous mobility shift assay was used to measure serum infliximab concentrations and ATI levels in 230 serum samples from 71 pediatric IBD patients. A subset of these children (n=31) also had 6 serial trough infliximab measurements, each taken prior to an infusion. A 5 mg/kg induction dose of infliximab was administered at Weeks 0, 2, and 6, followed by maintenance dosing every 8 weeks.

ATIs were detected in 20.4% of the serum samples (range, 0.28–800+ U/mL) and in 29.6% of the 71 children. Of the 47 ATI-positive serum samples, 8 also demonstrated measurable infliximab serum concentrations (range, 0.77–19.27 μg/mL). In the subset of children with serial trough level measurements, 8 had ATI-positive serum samples. Among ATI-positive samples, the median infliximab serum concentration was 0 μg/mL; in contrast, the median infliximab serum concentration among ATI-negative samples was 2.55 μg/mL (P<.0001). None of the ATI-positive samples exhibited infliximab serum concentrations of 3 μg/mL or higher, while 45% of the ATI-negative samples had infliximab levels of 3 μg/mL or higher. ATI-positive patients also had CRP levels that were approximately 1.5-fold higher than CRP levels in ATI-negative patients. A linear regression model found that a majority (88%) of children in the subset of patients with serum infliximab concentrations of 3 μg/mL or higher showed a decrease in CRP levels.

In conclusion, the investigators showed that ATI positivity may be a predictor of lower infliximab levels and increased CRP levels in pediatric IBD patients. As expected, higher infliximab levels (≥3 μg/mL) correlated with lower CRP levels. Importantly, this novel homogeneous mobility shift assay allowed simultaneous detection of serum infliximab concentrations as well as ATIs.

Reference

1. Veres G, Kaplan JL, De Greef E, et al. New assay to detect infliximab levels and anti-infliximab antibodies from a single serum sample is useful in measuring efficacy of treatment with infliximab in children with IBD. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Sa2037.

ABSTRACT SUMMARY Association of Serum Infliximab and Antibodies to Infliximab to Long-Term Clinical Outcome in Acute Ulcerative Colitis

In a poster presented at the 2012 DDW meeting, Sanjay Murthy and colleagues used a newly developed homogeneous mobility shift assay to assess the relationships among trough infliximab levels, ATI levels, and long-term clinical outcomes in patients with acute UC.¹ A total of 134 patients with corticosteroid-refractory acute UC were included in this analysis; 103 patients had pancolitis, and 31 patients had disease limited to the splenic fixture. All patients had received 5 mg/kg infliximab induction therapy on Weeks 0, 2, and 6, followed by scheduled maintenance therapy. Corticosteroid-free remission (defined as a Mayo Clinic score of 0) and colectomy were used as endpoints in this evaluation. At baseline, the median Mayo Clinic score was 9 points (range, 6–12 points).

After a median follow-up period of 19.9 months (interquartile range, 7.6–47.4 months), 43.3% of patients were in corticosteroid-free remission, and 39.6% had undergone colectomy. The median time to colectomy was 6.5 months (IQR, 2.3–13.4 months). Among 125 patients with evaluable serum samples, 54.4% (n=68) had detectable trough levels of serum infliximab. Of these 68 patients, 6 patients (8.8%) also had detectable levels of ATIs. Of the 57 patients (45.6%) who had undetectable trough serum infliximab levels, 45 patients (78.9%) were ATI-positive, and 12 patients (21.1%) were ATI-negative.

Importantly, the investigators showed that a trough infliximab level above 2 μg/mL was associated with a higher rate of corticosteroid-free remission compared to a trough infliximab level of 2 μg/mL or lower (69% vs 16%; P<.001). This relationship was sustained throughout the follow-up period. In contrast, a trough infliximab level below 2 μg/mL was significantly associated with an increased risk for colectomy compared to a trough infliximab level above 2 μg/mL (64% vs 13%; P<.001).

Reference

1. Murthy S, Kevans D, Seow CH, et al. Association of serum infliximab and antibodies to infliximab to long-term clinical outcome in acute ulcerative colitis. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Sa2047.

Accelerated Step-Care Therapy with Early Azathioprine Versus Conventional Step-Care Therapy in Crohn’s Disease: A Randomized Study

Three main strategies have been widely proposed to treat CD: (1) conventional step-up therapy, (2) an early top-down strategy, and (3) an accelerated step-up strategy. In the third paradigm, immunosuppressive agents (particularly azathioprine) are prescribed concomitantly with the first course of corticosteroids.

The strongest evidence supporting the accelerated step-up strategy is provided by a study from Markowitz and colleagues.¹ In this prospective, double-blind, placebo-controlled trial, pediatric patients who received 6-mercaptopurine had a shorter duration of corticosteroid use compared to patients who received placebo (observed-to-expected ratio, 0.73 days with prednisone vs 1.34 days with prednisone; P<.001). Additionally, while the rate of remission was similar with both treatment strategies (89% in both groups), the rate of relapse after remission was much lower in the 6-mercaptopurine–treated group compared to the placebo group (9% vs 47%; P=.007).

However, these results were not recapitulated in the Spanish AZTEC trial, which assessed early use of azathioprine versus placebo in adults who had been recently diagnosed with CD.² There was no significant difference in this study’s primary endpoint of sustained clinical remission (defined as a CDAI score <150 points at 18 months) between patients treated with azathioprine and those who received placebo (67.7% vs 57.1%; P=.2). Further, a nonresponder imputation analysis (in which missing scores were considered as treatment failures) showed even lower rates of sustained remission for both the azathioprine and placebo groups (44.1% vs 38.1%, respectively; P=.5). However, one benefit of early azathioprine therapy was an associated reduction in the cumulative dose of corticosteroids compared to the placebo group.

Given these findings, Jacques Cosnes and colleagues conducted a multicenter, open-label, randomized study to compare an azathioprine-based, accelerated step-up strategy with conventional step-up therapy in patients with early CD. Results of this trial were presented at the 2012 DDW meeting.³

All patients were recruited from multiple centers throughout France and Belgium. Patients enrolled in this study were at least 18 years of age at diagnosis, had been diagnosed with CD less than 6 months prior to enrollment, had not been previously treated with immunosuppressants, and had not previously undergone surgery. Additionally, patients were required to meet at least 2 of the following conditions, which predicted a high risk for the development of disabling disease: requirement of corticosteroids at first disease flare, age less than
40 years, and perianal disease.

Enrolled patients were randomized to either conventional step-up management or accelerated step-up management; in the latter group, the starting azathioprine dose was 2.5 mg/kg. The primary study endpoint was remission rate, which was strictly defined as no active disease, no requirement for corticosteroids, no treatment with anti–TNF-α therapy, no hospitalization-induced disease, no symptomatic perianal lesions, and no abdominal or perianal surgery.

A total of 147 patients were randomized to treatment. Five patients withdrew consent. Of the remaining 142 patients, 66 patients in the accelerated step-up arm and 68 patients in the conventional step-up arm were evaluable with at least 3 months of follow-up. At baseline, patients did not have active disease and demonstrated normal hemoglobin levels and normal or slightly elevated CRP levels.

The median proportion of patients who achieved remission was very similar between the 2 treatment groups. The accelerated step-up arm showed a trend toward a higher median remission rate during the first year of therapy, but this difference did not reach statistical significance and was not maintained over the course of follow-up. Likewise, there were no differences between arms in terms of median CDAI scores, serum CRP levels, or the median time to first introduction of anti–TNF-α therapy or first abdominal surgery. Overall, this study showed that an accelerated, azathioprine-based, step-up strategy was not associated with improvement in CD remission rates compared to a conventional step-up treatment strategy.

References

1. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000;119:895-902.

2. Sans M, Lopez-San Roman A, Esteve M, Bermejo A, Garcia-Sanchez V. Early use of azathioprine has
a steroid-sparing effect on recently diagnosed
Crohn’s disease patients. Presented at Digestive Disease Week; May 7–10, 2011; Chicago, Illinois. Abstract 590.

3. Cosnes J, Bourrier A, Laharie D, et al. Accelerated step-care therapy with early azathioprine (AZA) vs. conventional step-care therapy in Crohn’s disease. A randomized study. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943c.

ABSTRACT SUMMARY One Third of Patients Treated with Adalimumab or Infliximab for Crohn’s Disease or Ulcerative Colitis Permanently Dose Escalate Due to Loss of Response

Despite the significant efficacy of infliximab and adalimumab for the treatment of IBD, many patients lose response to these drugs. In a poster presented at the 2012 DDW meeting, Darryl Fedorak and colleagues reported the findings of a retrospective chart review in which they sought to determine the incidence of loss of response among patients treated with either of these 2 agents.¹ They further evaluated these charts to determine how many patients required dose escalation.

The investigators identified 363 patients who met the inclusion criteria for this study. All enrolled patients had an initial response to induction dosing with either infliximab (5 mg/kg administered at Weeks 0, 2, and 6) or adalimumab (160 mg and 80 mg administered at Weeks 0 and 2, respectively). Patients also had to have advanced to scheduled maintenance therapy (every 8 weeks mwith infliximab or every
2 weeks with adalimumab), achieved a stable corticosteroid-free clinical benefit that was durable for a minimum of 6 months, and exhibited a loss of response to their anti–TNF-α therapy. Finally, enrolled patients had to have sufficient follow-up to allow assessment of ongoing wellness and/or disease relapse with dose-escalated treatment.

At the time of the analysis, 65% of infliximab-treated patients remained in remission while on infliximab maintenance therapy at a dose of 5 mg/kg infliximab every 8 weeks. Similarly, 72% of adalimumab-treated patients were in remission on maintenance therapy with 40 mg adalimumab every other week. Thirty-five percent of patients who received infliximab required dose escalation (to 5 mg/kg every 4 weeks). Twenty-eight percent of adalimumab-treated patients required dose escalation (to 40 mg weekly). There was no significant difference in the rates of dose escalation between UC and CD patients. Further, a Kaplan-Meier plot found no significant difference in the time to treatment failure between infliximab and adalimumab (log-rank test, P=.56). Finally, dose de-escalation was uncommon. Only 7 infliximab-treated patients underwent dose de-escalation to the original doses; none of the adalimumab-treated patients underwent dose de-escalation.

Reference

1. Fedorak DK, Osatiuk P, Wong K, et al. One third of patients treated with adalimumab or infliximab for Crohn’s disease or ulcerative colitis permanently dose escalate due to loss of response. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract Sa2049.

PIANO: A 1,000-Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators and Biologic Therapy

Many women with IBD are of childbearing age, and previous studies have shown that these women have increased risks of adverse pregnancy outcomes and labor and/or delivery complications compared to women in the general population. Whenever possible, IBD medications are continued during pregnancy in order to achieve or maintain remission, but the safety of immunomodulator and/or biologic therapy during pregnancy has not been comprehensively studied.

At the 2012 DDW meeting, Uma Mahadevan summarized results from a study designed to more accurately determine the safety of immunomodulator and biologic therapy during pregnancy.¹ This study enrolled a large prospective cohort of pregnant women with IBD (N=1,115) who were identified from 30 member sites of the Crohn’s and Colitis Foundation of America; 57% of these patients had CD, and 40% had UC. Data were collected by telephone or through an in-person questionnaire at several time points: at intake, during each trimester of pregnancy, at delivery, and every 4 months during the first year of the child’s life. The mother’s medical history was also recorded, including medication exposure, IBD duration, and disease activity and complications during pregnancy and the postpartum period. Pregnancy outcomes, maternal disease course, newborn complications, and growth and developmental milestones were recorded for the first
year after birth.

Patients were divided into 4 categories based on their drug exposure between conception and delivery: (1) unexposed patients (N=306) who did not receive immunomodulator or biologic therapy during the study but were instead treated with mesalamine, corticosteroids, or antibiotics; (2) immunomodulator-treated patients (N=204) who received either azathioprine or 6-mercaptopurine; (3) anti–TNF-α–treated patients (N=291) who received either infliximab, adalimumab, certolizumab pegol, or natalizumab during the study; or (4) combination-treated patients (N=75) who received both immunomodulators and anti–TNF-α agents during the study. At the time of the 2012 DDW presentation, 896 women had completed their pregnancies.

The demographics of the mothers differed across treatment groups. More CD patients had been exposed to biologic therapy (43%) compared to UC patients. Among UC patients, 65–75% had inactive disease during pregnancy, and fewer patients had inactive disease at the beginning of pregnancy than 12 months postpartum. In contrast, more CD patients had inactive disease during pregnancy (80–90%), and these patients were more likely to have inactive disease at the beginning of pregnancy than postpartum.

After adjusting for the effects of the underlying disease, most adverse incidents—including spontaneous abortions or congenital anomalies—did not occur at a significantly increased rate among women enrolled in this study compared to community-based or national rates. However, there were a few exceptions: Women in this study had a higher rate of Caesarean sections, and their babies had a higher rate of neonatal intensive care unit stay. Also, there were higher rates of spontaneous abortions and Cesarean sections in the anti–TNF-α group, and there was a higher rate of preterm births among women in the combination therapy group.

While babies of mothers with CD showed no increase in any complications or adverse effects, a nearly 5-fold higher rate of spontaneous abortion was observed among mothers with UC who were treated with anti–TNF-α agents. Further, UC mothers in the combination therapy group had an increased risk of any complication—including preterm birth, low birth weight, and neonatal intensive care unit stay—after the analysis adjusted for disease activity.

There were no significant differences in the growth characteristics of the babies throughout their first year, including height, weight, and developmental measurements at 4, 9, and 12 months of age (adjusted for maternal age and disease activity). In addition, no association was found between congenital anomalies and drug exposure. Finally, the rate of infections among the infants was not significantly affected by drug exposure; however, when certolizumab pegol was removed from the analysis, the rate of infections in babies at 1 year of age was higher among babies whose mothers were in the combination therapy group (relative risk, 1.38). Taken together, these results suggest that the mother’s disease may confer a higher risk to the fetus than the risks associated with the use of immunomodulator or biologic therapy.

Reference

1. Mahadevan U, Martin CF, Sandler RS, et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 865.

Commentary

William J. Sandborn, MD

The 2012 DDW meeting—which was held May 19–22, 2012 in San Diego, California—included a number of important studies, several of which are summarized in this supplement. While all of these data are relevant and worthy of consideration, the 3 studies I feel are most noteworthy are highlighted below.

First, the presentation on azathioprine by Jacques Cosnes suggests that this drug may be less effective than was previously thought.¹ Azathioprine has been used to treat CD in a few centers since the early 1980s and worldwide since the early 1990s, but the FDA has never approved azathioprine as a treatment for CD. In large part, this lack of approval stems from the fact that azathioprine has been available as a generic drug since the late 1990s, so pharmaceutical companies have had little incentive to perform the large clinical trials needed to definitively demonstrate azathioprine’s safety and efficacy for the treatment of CD. In the absence of large clinical trials, clinicians have based their use of azathioprine on smaller, investigator-initiated trials, which has led to some challenges. Specifically, we lack data to show that the clinical benefits of azathioprine monotherapy outweigh its risks—which include nonmelanoma skin cancer and non-Hodgkin lymphoma, according to recent studies.

The French study presented by Cosnes helps to answer this question by testing whether early and more extensive use of azathioprine in patients with CD is effective. When prescribing anti–TNF-α drugs, many clinicians use a “top-down” treatment strategy, in which anti–TNF-α therapy is initiated early in the course of CD in an effort to improve clinical outcomes and potentially change the natural history of the disease. The study presented by Cosnes aimed to test whether the same goal could be achieved with early use of azathioprine combined with a tapering course of prednisone. Early azathioprine treatment was compared to a traditional “step-up” treatment strategy, in which clinicians started with less effective therapies, then advanced to prednisone, and finally added azathioprine, if it was needed.

While studies have demonstrated that early use of anti–TNF-α therapy leads to better clinical outcomes, the data presented by Cosnes showed that early use of azathioprine was not more effective than the classical step-up treatment strategy. This finding confirmed that of a similar study presented by Miquel Sans at the 2011 DDW meeting, which achieved essentially the same result.² Thus, 2 randomized trials in adults have shown that early use of azathioprine does not improve clinical outcomes and does not change the course of CD when compared to later use of azathioprine (or, in the case of the Sans trial, to placebo).

Given that other trials have shown some degree of benefit with azathioprine, I think it is probably incorrect to conclude that azathioprine has no efficacy. However, these 2 trials show that the magnitude of efficacy with azathioprine is considerably less than was previously believed. When these data are considered alongside emerging data about the toxicity of azathioprine—which suggest that the side effects of this drug are greater than was initially thought—the totality of the benefit versus risk of azathioprine monotherapy certainly appears less favorable now than it did 5–10 years ago. In contrast, the SONIC trial clearly showed that azathioprine combined with anti–TNF-α therapy was more effective than monotherapy with either drug alone.³ Thus, clinicians may want to reconsider how they use azathioprine in clinical practice, changing from azathioprine monotherapy to combination therapy with azathioprine plus an anti–TNF-α drug.

The second DDW presentation that deserves special mention is the GEMINI I trial, which studied vedolizumab for the treatment of UC. In a 2005 paper published in The New England Journal of Medicine, Brian Feagan and coauthors presented data from a phase II study that demonstrated the efficacy of vedolizumab in patients with UC who were failing first-line therapy with mesalamine.⁴ This study was the first positive study to show that blocking lymphocyte trafficking to the gut could effectively treat UC; however, it did not assess vedolizumab as maintenance therapy, and it did not include treatment-refractory patients. The GEMINI I trial was conducted to address these gaps.

In a presentation at the 2012 DDW meeting, Feagan definitively showed that vedolizumab is effective for inducing response, remission, and mucosal healing in a cohort of outpatients with severe UC, approximately half of whom were failing anti–TNF-α therapy.⁵ Data on the use of vedolizumab for maintenance therapy will be presented at the American College of Gastroenterology (ACG) meeting
later this year.

One major benefit of vedolizumab is its apparent specificity for the gut, which will hopefully prevent some of the side effects that have been associated with natalizumab. Because natalizumab blocks lymphocyte trafficking in the brain as well as in the gut, this drug can reduce immune surveillance in the brain, which puts patients at risk for progressive multifocal leukoencephalopathy (PML). This risk has precluded the widespread use of natalizumab for the treatment of CD. Because vedolizumab is gut-specific, however, it blocks lymphocyte trafficking and prevents inflammation in the gut without increasing the risk for PML. Overall, the vedolizumab data presented at DDW suggest that this drug is effective for the treatment of UC, even in patients who have failed prior anti–TNF-α therapy—a difficult-to-treat group that is frequently encountered in clinical practice. Hopefully, vedolizumab will be approved for clinical use within the next 1–2 years.

Finally, the golimumab data from the PURSUIT-SC trial also deserve careful consideration.⁶ Currently,
3 anti–TNF-α drugs are approved in the United States for the treatment of CD: infliximab, adalimumab, and certolizumab pegol. However, only infliximab is approved for the treatment of UC, which limits clinicians’ ability to provide optimal patient care. In an effort to give clinicians more treatment options for UC, the new drug golimumab was recently evaluated in a phase II/III induction study, the results of which were presented during the 2012 DDW meeting.

This trial demonstrated that golimumab is effective for inducing response, remission, and mucosal healing in a cohort of outpatients with moderate-to-severe UC who were naïve to anti–TNF-α therapy. Data from the maintenance phase of this study will be presented at the ACG meeting later this year. The data from the PURSUIT-SC study should be sufficient to support regulatory review of golimumab, and this drug will likely be approved within the next 1–2 years.

In addition to these data on golimumab, the FDA is also currently reviewing data that support the use of adalimumab as a treatment for UC, and I am hopeful that both drugs will receive FDA approval for the treatment of UC in the near future. At that point, a range of anti–TNF-α drugs will be available for the treatment of UC—including some drugs that can be administered subcutaneously—which would give clinicians the same degree of flexibility when treating UC that they currently enjoy when treating CD.

In conclusion, I think both Cosnes’ study of azathioprine and the PURSUIT-SC trial have immediate relevance to clinical practice, as both studies provide data that could be helpful when clinicians are deciding on therapy for specific patients. As clinical practice evolves, we may need to consider a reappraisal of some of the drugs currently in use, like azathioprine, and we will also need to make room for a variety of new treatment options—both new members of existing classes of drugs, like golimumab, and new drugs in entirely new classes, like vedolizumab.

References

1. Cosnes J, Bourrier A, Laharie D, et al. Accelerated step-care therapy with early azathioprine (AZA) vs. conventional step-care therapy in Crohn’s disease. A randomized study. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943c.

2. Sans M, Lopez-San Roman A, Esteve M, Bermejo A, Garcia-Sanchez V. Early use of azathioprine has a steroid-sparing effect on recently diagnosed Crohn’s disease patients. Presented at Digestive Disease Week; May 7–10, 2011; Chicago, Illinois. Abstract 590.

3. Colombel JF, Sandborn WJ, Reinisch W, et al; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383-1395.

4. Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 2005;352:2499-2507.

5. Feagan BG, Rutgeerts PJ, Sands BE, et al. Vedolizumab induction therapy for ulcerative colitis: results of Gemini I, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943b.

6. Sandborn W, Feagan B, Marano C, et al. A phase 2/3 randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of subcutaneous golimumab induction therapy in patients with moderately to severely active ulcerative colitis: PURSUIT-SC. Presented at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract L6100.