Gastroendonews: Tea Leaves No More: Biologics Head-to-Head Produces a Winner
In the first head-to-head trial of biologic treatments for inflammatory bowel disease, vedolizumab (Entyvio, Takeda) was nearly 50% more effective than adalimumab (Humira, AbbVie) in inducing clinical and mucosal remission in patients with moderate to severe ulcerative colitis…
They enrolled 771 patients with moderate to severe ulcerative colitis in the VARSITY study and randomly assigned them to receive 52 weeks of treatment with either vedolizumab or adalimumab…
They had failed other conventional therapies, including 25% in each group that had received an anti–tumor necrosis factor (TNF) agent…
- 31.3% of vedolizumab recipients and 22.5% of those taking adalimumab were in clinical remission after 52 weeks (P=0.0061). Clinical remission was defined as a complete Mayo score of 2 or lower and no subscore greater than 1
- Nearly 40% of patients who received vedolizumab achieved mucosal healing at 52 weeks, compared with 27.7% of adalimumab recipients (P=0.0005).
My take: This study provides a rationale for vedolizumab to be used as a first-line biologic agent for ulcerative colitis.
A recent retrospective study (A Favale et al. Comparative Efficacy of Vedolizumab and Adalimumab in Ulcerative Colitis Patients Previously Treated With Infliximab Inflammatory Bowel Diseases, izz057, https://doi.org/10.1093/ibd/izz057 Published: 01 April 2019) suggests that vedolizumab is more effective for ulcerative colitis with secondary infliximab failure.
Here’s the abstract:
Adalimumab (ADA) and vedolizumab (VDZ) have shown efficacy in moderate to severe ulcerative colitis (UC) patients who failed infliximab (IFX). Although, a comparative efficacy evaluation of ADA and VDZ in this clinical setting is currently missing.
The aim of this study is to compare the efficacy of ADA and VDZ in patients affected by UC who failed IFX.
Clinical records of UC patients from 8 Italian IBD referral centers who failed IFX and were candidates to receive either ADA or VDZ were retrospectively reviewed. The primary end point was therapeutic failure at week 52. Secondary end points included therapy discontinuation at weeks 8, 24 and 52, the discontinuation-free survival, and safety.
One hundred sixty-one UC patients, 15 (9.2%) primary, 83 (51.6%) secondary IFX failures, and 63 (39.2%) IFX intolerants were included. Sixty-four (40%) patients received ADA and 97 (60%) VDZ as second line therapy. At week 52, 37.5% and 28.9% of patients on ADA and VDZ, respectively, had therapeutic failure (P = 0.302). However, the failure rate was significantly higher in the ADA group as compared with VDZ group among IFX secondary failures (48.0% ADA vs 22.4%VDZ, P = 0.035). The therapy discontinuation-free survival was significantly higher in the group of IFX secondary failures who received VDZ as compared with ADA at both the univariate (P = 0.007) and multivariate survival analysis (OR 2.79; 95% CI, 1.23–6.34; P = 0.014). No difference in the failure and biologic discontinuation-free survival was observed in the IFX primary failure and intolerant subgroups.
October 31, 2018: FDA Approves Sandoz’s Biosimilar Adalimumab, Hyrimoz
The FDA has approved Sandoz’s biosimilar adalimumab, Hyrimoz (adalimumab-adaz).
The drug has been approved to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn disease, ulcerative colitis, and plaque psoriasis…
Despite today’s approval, US patients will have to continue to wait for access to Hyrimoz, as the biosimilar will not enter the US market until 2023. Earlier this month, Sandoz announced a global settlement of patent disputes with AbbVie over the drug. While the settlement allowed Sandoz to launch Hyrimoz in the European Union on October 16, 2018, it forestalled US market entry until September 30, 2023.
My take: Why will this biosimilar be allowed in Europe but not U.$?
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G Horneff et al. J Pediatr 2018; 201: 166-75. This industry-funded analysis of 577 pediatric patients who received adalimumab (1440 patient-years) identified no new safety signals. The most common serious infection was pneumonia (0.6 events per 100 patient-years). The most common adverse events were respiratory tract infections/nasopharyngitis. Serious infections were more common in the subset of patients with Crohn’s disease (CD), (n=189), occurring in 13%.
PS Dulai et al. Gastroenterol 2018; 155: 687-95. This study, using data from GEMINI 2 phase 3 trial with 814 patients, developed a clinical prediction tool for determining the likelihood of a clinical response to vedolizumab. Common predictors for response:
- No prior bowel surgery
- No prior anti-TNF exposure
- No prior fistulizing disease
- Higher baseline albumin
- Lower baseline CRP
R Matro et al. Gastroenterol 2018; 155: 696-704. The authors performed a prospective study of women with IBD and their infants (n=72). They “detected low concentrations of infliximab, adalimumab, certolizumab, natalizumab, and ustekinumab in breast milk samples. We found breastfed intants of mothers on biologics, immunomodulators, or combination therapies to have similar risks of infection …compared to non-breastfed infants or infants unexposed to these drugs.”
A recent clinical review (X Roblin et al. Inflamm Bowel Dis 2018; 24: 1904-9) examines the utility of proactive drug monitoring of anti-TNF therapy in inflammatory bowel disease.
The authors note that several observational trials suggested that proactive drug monitoring would help optimize the effect of anti-TNF therapy, especially infliximab. However, two randomized controlled clinical trials, TAXIT (n=273) and TAILORIX (n=122), were not able to show long-term benefit from proactive therapeutic monitoring.
At the same time, the authors note that a recent trial (Ungar B et al. Clin Gastroenterol Hepatol 2016; 14: 550-7, e2) has shown that infliximab trough levels >5 mcg/mL and adalimumab levels >7.2 mcg/mL identified mucosal healing with 85% specificity. Higher cutoffs showed only minimal further increase in mucosal healing rates.
My take: To this point, controlled trials have not shown that proactive drug monitoring of anti-TNF therapy is beneficial; this review explains the design and limitations of these studies. My personal view is that more studies are needed to know if proactive drug monitoring is worthwhile. Proactive drug monitoring may be more useful in children/adolescents than adults due to much greater variation in size and dosing.
A recent commentary on therapeutic drug monitoring (from KT Park Twitter Feed): Therapeutic Targets in IBD
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K Watanabe et al. Clin Gastroenterol Hepatol 2018; 16: 542-9.
The DIAMOND study evaluated monotherapy with adalimumab (n=85) compared with combination therapy of adalimumab with azathioprine (n=91).
- In this subanalysis of patients with moderate and severe Crohn’s disease (CD), endoscopic response (defined by SES-CD drop of at least 8 points or SES-CD <4) was significantly higher at week 26: 71.6% vs 54.4%. The OR for endoscopic response was 2.12 at week 26 with combination therapy.
- At week 52 the endoscopic response difference was not statistically significant: 60% vs. 50%.
- Similarly, mucosal healing was more common (but not statistically significant) in the combination group compared with monotherapy: 20.9% vs 103% at week 26, and 21.5% vs 12.2% at week 52.
- While not statistically significant, the combination group had ADA trough that was higher (7.6 compared with 6.5).
My take: The results described above for endoscopic responses and mucosal healing rates are depicted in figure 2 (I do not have a digital copy of figure or permission to use). After one looks at this figure, depicting the data noted above, there certainly appears to be an advantage for the use of combination therapy in patients with moderate-to-severe CD.
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I have not independently verified the claims on this tweet
From ImproveCareNow: Real-World Experience with Adalimumab
A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…
- At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission
- At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission
- At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission
- At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission
- At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission
No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.
EC Maxwell et al. JPGN 2017; 65: 299-305 CHOP experience with diverting ileostomy for severe IBD (2000-2014).
- In this retrospective study, a diverting ileostomy in 24 patients had improvement: 71% –>22% on chronic steroids, improved growth, hemoglobin, blood transfusion and hospitalization.
- 10 patients underwent subsequent colectomy, 7 had successful reanastomosis, and 7 remain diverted.
- Diversion allowed a definitive diagnosis in 7 subjects (initially 13 patients were considered IBD-U).
- Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.
- One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.
- The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.
A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.
L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery. Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.
I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects. Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.
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