Tag Archives: Ulcerative colitis

Vedolizumab and Infliximab: Expected Dosing When Switching From IV to SC Routes

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Z Wang et al. Clin Gastroenterol Hepatol 2023; 3188-3190. Therapeutic Drug Monitoring Can Guide the Intravenous-to-Subcutaneous Switch of Infliximab and Vedolizumab: A Simulation Study

The authors performed population pharmacokinetic (popPK) simulations to determine optimal dosing recommendations.

Key points:

  • Infliximab: “The Q2W SC dosing regimen of infliximab has been selected with the purpose of exceeding a C,trough,ss of 5 mg/L.” This tends to align with 5 mg/kg Q8W IV dosing.
  • Infliximab: “Patients on Q6W or Q8W IV infliximab can safely switch to Q2W SC infliximab…only patients on Q4W IV infliximab need Q1W SC dosing”
  • Vedolizumab: “Only patients on Q4W IV vedolizumab should switch to Q1W SC dosing”
  • Both agents: “Switching 4 instead of 8 weeks after the last IV dose can hit SS[steady state] faster, thereby avoiding the risk of temporary underexposure.”

My take: It is still important to see how switching from IV to SC route affects clinical outcomes in real-world cohorts. This study, though, does provide a good starting point when trying to provide the right dose frequency to achieve good therapeutic troughs.

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Japanese Maple tree

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

New IBD Medication: Guselkumab for UC (QUASAR study)

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Previous work has established Guselkumab, a IL-23p19 subunit antagonist for Crohn’s disease (Guselkumab: Expanding the GALAXI of Treatments for Crohn’s Disease).

Peyrin-Biroulet et al now provide data showing its efficacy for ulcerative colitis (UC): Gastroenterol 2023; 165: 1443-1457. Open access! Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study

Background/Methods: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. In this double-blind, placebo-controlled, dose-ranging, induction study, adult patients (n=313), with median disease duration of 7.5 years, were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8.

Key findings:

  • Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). (Patients received IV induction at 0,4, and 8 weeks)
  • Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12
  • Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24 (after another dose of guselkumab (2nd dose SC). Thus, by week 24, 80.2% (81/101) of patients in the 200 mg IV induction and 78.5% *84/107) in the 400 mg IV induction had a clinical response.
  • Clinical response was noted as early as 2 weeks (first timepoint assessed)
  • Safety was similar among guselkumab and placebo groups.

My take: This is an era with rapidly expanding medical treatments for inflammatory bowel disease; it should help reduce the problem of individuals who are refractory to available treatments.

FDA Approves Etrasimod for Ulcerative Colitis

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GI & Hepatology News, November 2023: FDA OKs two new treatments for UC

An excerpt:

In October, the FDA approved etrasimod (Velsipity, Pfizer) for moderate to severe active UC in adults. Etrasimod, an oral sphingosine-1-phosphate (S1P) receptor, binds with high affinity to receptors 1, 4, and 5. It is the second agent in the S1P class approved for UC. The other agent, ozanimod (Zeposia, Bristol-Myers Squibb), which was approved for moderate to severe active UC in May 2021, is an S1P receptor modulator that is selective for the S1P1 and S1P5 receptors located on endothelial cells and oligodendrocytes, respectively.

Etrasimod’s approval was based on safety and efficacy data from two randomized, double-blind, placebo-controlled phase 3 trials ― ELEVATE UC 52 trial, and ELEVATE UC 12 trial. The Lancet published full results from the two trials on March 2. Both trials enrolled patients with UC who had previously failed or were intolerant of at least one conventional, biologic, or Janus kinase (JAK) inhibitor therapy.

In ELEVATE UC 52, clinical remission at 12 weeks occurred in 27% of patients taking etrasimod, vs 7% of patients taking a placebo (20% difference; P ˂.001). At week 52, remission rates were 32% with active treatment, vs. 7% with placebo (26% difference;
P ˂ .001).

In ELEVATE UC 12, clinical remission was achieved among 26% of patients who received etrasimod, vs 15.0% of patients who received placebo (11% difference; P < .05).

The approved recommended dose is 2 mg once daily. The most common side effects of etrasimod are headache, elevated values on liver tests, worsening of UC, SARS-CoV-2 infection, dizziness, pyrexia, arthralgia, abdominal pain, and nausea

Reference: WJ Sandborn et al. The Lancet 2023; DOI:https://doi.org/10.1016/S0140-6736(23)00061-2. Open Access! Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

My take: It is not exactly clear where etrasimod or ozanimod should be positioned for ulcerative colitis therapy as several other drug classes have much higher response rates.

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Next time someone says that they are receiving therapy, perhaps I will be able to say ‘me too.’

U.S. IBD Prevalence: 7 in 1000

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JD Lewis et al. Gastroenterology 2023 Nov;165(5):1197-1205.e2. doi: 10.1053/j.gastro.2023.07.003. Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States

This “INPUT” (INcidence, Prevalence, Treatment and OUTome in Patients with IBD) study used 4 different data sets to provide “the clearest depiction to date of IBD [epidemiology] in the U.S.

Key findings:

  • The age-, sex- and insurance-standardized prevalence of IBD was 721 per 100,000 population. This equates to estimated 2.39 million Americans with IBD.
  • Sub-category prevalence: the prevalence of IBD per 100,000 population was 812 in White, 504 in Black, 403 in Asian, and 458 in Hispanic Americans.

My take: The prevalence of IBD continues to increase and the U.S. has one of the highest rates in the world.

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When is the Right Time to De-escalate Dose of Tofacitinib for Ulcerative Colitis?

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A Yu et al. Clin Gastroenterol Hepatol 2023; 21: 3115-3124. Open Access! Real-World Experience With Tofacitinib Dose De-Escalation in Patients With Moderate and Severe Ulcerative Colitis

On May 30, 2018, the US Food and Drug Administration (FDA) expanded the indication of tofacitinib (Xeljanz; Pfizer), an oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active ulcerative colitis. However, the optimal dosing remains unclear.

In this “real-world” study by Yu et al, a retrospective review of 162 patients was conducted (2012-2022). 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily.  The primary outcome was evidence of UC disease activity–related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch.

Key findings:

  • Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P = .81)
  • An induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41)
  • Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months

Discussion Points:

  •  “Although the product label recommends dose de-escalation after 8 or 16 weeks, clinical practice is variable in the real-world setting… In this retrospective real-world study of moderate to severe UC patients with almost half undergoing dose de-escalation, we observed that more than half of patients experienced a UC disease activity–related event within 12 months after dose de-escalation, particularly in patients with an induction course of fewer than 16 weeks and active endoscopic disease at 6 months after induction…”
  • ” Although dose de-escalation is preferable for long-term maintenance therapy to reduce the potential lifetime risk of medication-related adverse events [eg. VTE], it must be balanced with sustained remission to prevent short- and long-term disease-related complications.”
  • “In the OCTAVE study which reported higher rates of long-term remission, patients de-escalated only after having shown clinical and endoscopic remission after 52 weeks on tofacitinib 10 mg twice daily”

My take (borrowed from authors):  “Emphasis should be placed on clinical and endoscopic evidence of improvement before consideration of dose de-escalation to ensure the highest probability of treatment success.” This advice, though, may conflict with product labelling which states that “tofacitinib induction with 10 mg twice daily beyond 16 weeks is not recommended; in fact, it is recommended to stop after 16 weeks if adequate response has not been achieved.”

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Belem Tower, Lisbon

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Genetic Test to Help Determine Need for Combination Therapy with Anti-TNF

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V Solitano et al. Clin Gastroenterol Hepatol 2023; 21: 3019-3029. HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Key findings:

  • On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75) with considerable heterogeneity (I2 = 62%) (low certainty evidence).
  • In addition, patients with HLA-QQA1*05 variants had clinical loss of response (LOR) in 67% compared to 30% in those without this variant (wild-type); thus, a 124% higher risk of LOR.
  • Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively
  • Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association.

My take:

  • The ~40% of individuals with HLA-DQA1*05 variants are at higher risk of LOR and are more likely to benefit from both therapeutic drug monitoring and probably from use of combination (with immunomodulator) therapy.
  • The positive predictive value (30%) is low indicating that the majority of patients with these variants will not develop anti-drug antibodies within 12 months.
  • In those with negative testing for HLA-DQA1*05 (~60%), the higher negative predictive value indicates a patient is more likely to do well with monotherapy.
  • HLA-DQA1*05 testing is available commercially (usually part of Celiac HLA typing).

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This is the Initiation Well at Quinta da Regaleira in Sintra, Portugal.
It is pretty cool because it seems to start at ground level and then goes down many floors.
There is an exit to a number of tunnels at the lower level.

What’s Changing in IBD Care: Hospitalization Rates and Authorizations

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The Good News:

MJ Buie et al. Inflamm Bowel Dis 2023; 29: 1536-1545. Open Access! Hospitalization Rates for Inflammatory Bowel Disease Are Decreasing Over Time: A Population-based Cohort Study

This population-based administrative data cohort study provides annual IBD hospitalization rates in Alberta, Canada.

Key findings:

  • From 2002-2003 to 2018-2019, all-cause hospitalization rates decreased from 36.57 to 16.72 per 100 IBD patients (Average Annual Percentage Change (AAPC), −4.18%)
  • Inflammatory bowel disease–related hospitalization rate decreased from 26.44 to 9.24 per 100 IBD patients (AAPC, −5.54%)
  • The absolute number of hospitalizations, however, likely did not improve because this is affected by the increase in IBD prevalence. In Alberta, there was a 3-fold increase from 2002 to 2018 (general population increased 1.4 fold during this period)

“The last 2 decades have seen the introduction of several advanced therapies with novel mechanisms of action.22 The introduction of these therapies has been accompanied by changes in management strategies that include earlier introduction of advanced therapies based on risk stratification, treat-to-target, and monitoring strategies.5,23–26 These advancements include risk stratification, allowing for earlier introduction of advanced therapies; proactive clinical management algorithms to monitor disease activity; and therapeutic drug monitoring allowing for continued concentration-based dosing.23–26The net effect of these medical advances shifted IBD management from the hospital to the outpatient setting.27“

The Bad News:

DK Choi et al. Inflamm Bowel Dis 2023; 29: 1658-1661. Delays in Therapy Associated With Current Prior Authorization Process for the Treatment of Inflammatory Bowel Disease

This retrospective study of 1693 prior authorizations (PAs) from 2020-2021. Key findings:

  • 1397 PA initially approved, 209 first-level PAs approved, 23 second-level PAs approve, and 11 external review requests approved. In total 97% (1640 of 1697) were approved
  • Dose escalations had the lowest approval rate of 67.6%
  • FDA approval had favorable OR for PA approval of 4.45
  • The median time to biologic initiation was 21 days, with appeals causing further delays to initiation

Median Days to Determination by Insurance Level:

  • Prior authorization: 11 days
  • First level appeal: 29 days
  • Second level appeal: 51 days
  • External review request: 73 days

My take: The PA process usually results in few denials (if pursued) but does result in significant delays in therapy. At the same time, these newer therapies have been associated with improvement in hospitalizations rates.

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Upadacitinib Works Quickly and with High Response

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D Ahuja et al. Am J Gastroenterol 2023; Open Access! Comparative Speed of Early Symptomatic Remission With Advanced Therapies for Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Network Meta-Analysis Thanks to Ben Gold for this article.

Key findings:

  • On network meta-analysis of 14 RCTs, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85–6.27), 4 (range of RR, 1.78–2.37), and 6 (range of RR, 1.84–2.79). 

This study has a number of limitations including the following:

  • Potential differences in patient-level characteristics between these trials
  • Symptoms may not always correlate with endoscopic findings
  • Data from some medications (eg. tofacitinib) were incomplete and not included

My take: This study indicates an impressive early symptomatic response to upadacitinib compared to other agents for ulcerative colitis.

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Thiopurines Efficacy in Children with Ulcerative Colitis

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FA Hanna et al. JPGN 2023; 77: 505-511. Thiopurines Maintenance Therapy in Children With Ulcerative Colitis: A Multicenter Retrospective Study

In this retrospective study with 133 children (2008-2019), typical dosing of thiopurines: azathioprine 2-2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kg/day. Patients with previous or concomitant treatment with 5-ASA were allowed in the study. 62% (n=83) of the cohort had pancolitis. Key Findings:

  • Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy
  • In the cohort in clinical remission, 67 and 51 patients had both CRP and calprotectin measurements at 1 year and end of follow-up. Sufficient biomarker response (CRP <1 mg/dL, calprotectin <250 mcg/g) was achieved by 44 (66%) and 44 (86%) at those two time points.
  • The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively
  • 8 of 133 (6%) stopped thiopurine therapy due to adverse effects

In their discussion, the authors make several points regarding efficacy and safety of thiopurines.

  • Many experts have advocated use of anti-TNF therapy agents for ulcerative colitis especially when 5-ASA medications are not effective.. This is based on higher efficacy and safety. With regard to safety, the authors note an “extremely low risk of lymphoma” citing a study from Israel in which children were followed until age of 30 years. No cases of hepatosplenic T-cell lymphoma were identified and the lymphoma rate was not statistically significant (O Atia et al. J Crohns Coliitis 2022; 16: 786-795 Open Access! Risk of Cancer in Paediatric onset Inflammatory Bowel Diseases: A Nation-wide Study From the epi-IIRN).
  • The authors note a recent review “rejected the hypothesis that initiation of biologic treatment later in the disease course correlates with lower response and remission rates in UC patients.”
  • Based on the efficacy and safety, the authors advocate for use of thiopurines “either early in the treatment course or as part of a de-escalation therapy…Thiopurines should be considered in the treatment of UC patients before the initiation of biologic drugs in most children.”

My take: In the U.S., it appears that thiopurine monotherapy, and even combination therapy, in pediatrics with IBD is used infrequently. Anti-TNF therapy with therapeutic drug monitoring is used routinely in patients if a 5-ASA is ineffective or not a good option. This article is a reminder that thiopurines are still a reasonable option. This would have been a good opportunity for a commentary in JPGN to add some context to this article regarding the role of these agents.

AGA guidelines for moderate-to-severe ulcerative colitis: “In adult outpatients with moderate to severe UC in remission, AGA makes no recommendation in favor of or against using biologic monotherapy or tofacitinib rather than thiopurine monotherapy for maintenance of remission.”

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Ospedaletti, Italy
Calanques, France