A previous blog post (Vedolizumab More Effective Than Adalimumb for Ulcerative Colitis) highlighted a preliminary report on the “VARSITY” study. The full report has now been published (BE Sands et al NEJM 2019; 381: 1215-26) and a little nuance is needed.
This double-blind, double-dummy randomized trial included 769 patients who underwent randomization to receive at least one dose of one of the study medications.
- At week 52, clinical remission was higher in the vedolizumab group: 31.3% compared to 22.5% for adalimumab
- Endoscopic improvement was better for vedolizumab: 39.7% compared to 27.7%
- Corticosteroid-free remission was better for adalimumab: 21.8% compared to 12.6% for vedolizumab
- dose escalation was not allowed during the study –this limitation likely favors vedolizumab compared to adalimumab
- previous exposure to an anti-TNF agent was allowed in up to 25% of patients
My take: In two of three key measures, vedolizumab outperformed adalimumab. This study provides a rationale for vedolizumab to be considered a first-line agent. That being said, in my clinical experience, infliximab is a much more frequently used anti-TNF agent in moderate-to-severe ulcerative colitis. So a head-to-head study with infliximab would be of interest.
The image below shows histologic remission differences at week 52
This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease. The first article (K Papmichael et al. Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.
Full Text Link: Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases
- For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
- Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response
Background/Rationale for pTDM:
- “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
- “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
- “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”
Table 4 Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease
- It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
- It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.
5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response
9-12: Ustekinumab -agreement only on ordering TDM in non-responders or those with loss of response
From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease
- Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
- Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
- Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
- Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
- Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance
My take: This article provides extensive literature to reinforce their recommendations. Most of the trough levels mentioned are minimum levels that need to be achieved.
The recommendations from the Canadian Association of Gastroenterology for luminal Crohn’s Disease in adults were published in two journals. R Panaccione et al. Clin Gastroenterol Hepatol 2019; 17: 1680-1713 and R Panaccione et al J Can Assoc Gastroenterol. 2019 Aug; 2(3): e1–e34.
Full text link : Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn’s Disease
A few of the 41 statement recommendations:
- 6. In patients with mild to moderate ileal and/or right colonic Crohn’s disease, we suggest oral budesonide beginning at 9 mg/day as first-line therapy to induce complete remission. GRADE: Conditional recommendation, low-quality evidence
- 20. In patients with moderate to severe luminal Crohn’s disease with risk factors of poor prognosis, we recommend anti-TNF therapy (infliximab, adalimumab) as first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 23. In patients with active Crohn’s disease, when starting anti-TNF therapy, we suggest it be combined with a thiopurine or methotrexate over monotherapy to improve pharmacokinetic parameters. GRADE: Conditional recommendation, very low-quality evidence for infliximab, very low-quality evidence for adalimumab
- 29. We suggest against switching between anti-TNF therapies in patients who are doing well on anti-TNF therapy. GRADE: Conditional recommendation, low-quality evidence
- 30. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend vedolizumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 34. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend ustekinumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 37-41: Authors against the use of probiotics, omega-3 fatty acids, marijuana, naltrexone and enteral nutrition/diet therapies.
Crater Lake and Wizard Island
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.$?
Related blog posts:
Zabriskie Point at Sunrise, Death Valley
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.”