Ustekinumab Effectiveness for Ulcerative Colitis Over Two Years

R Pannacionne et al. AP&T. 2020; https://doi.org/10.1111/apt.16119. Full text link: Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy

Methods: Overall, 399 (adult) “responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long‐term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44”

Key Findings:

  • Symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively ((Intent-to-treat population).
  • At week 44 of maintenance, measures of UC disease activity (eg Mayo scores) were generally comparable among patients randomised to ustekinumab q12w and q8w with 46.1% and 52.4% in clinical remission and 56.7% and 61.5% with endoscopic improvement respectively
  • Among randomised patients treated in the long‐term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid‐free
  • No new safety signals were observed
Steroid-free Remission (Intent-to-treat population)

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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

Stelara (Ustekinumab) Safety

F Poizeau et al. JAMA Dermatol. Published online September 9, 2020. doi:10.1001/jamadermatol.2020.2977. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti–Interleukin 12/23p40 Antibody Ustekinumab

Methods: “This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018.”

Key findings:

  • Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke).
  • Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59).
  • Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13).

My take: This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk; however, the study conclusions are limited as this was an observational study (not a randomized trial).

“Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease” & 14% of U.S. Infected with COVID-19

J Breton et al. Gastroenterology & Hepatology 2020; 16: 400-14. Full text: Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease

This is a terrific summary of biologic therapies for pediatric inflammatory bowel disease. Compared to adults, the pediatric data is much more limited.  This may affect recommendations.  For example, recent AGA guidelines for moderate to severe ulcerative colitis in adults suggests that either ustekinumab or tofacitinib is generally preferable as a 2nd line agent rather than vedolizumab in patients with primary infliximab failure (Blog post: AGA Guidelines: Moderate to Severe Ulcerative Colitis).  In the chart below, vedolizumab is recognized as a preferred 2nd line agent.

In the section on vedolizumab:

The favorable risk-benefit profile makes vedolizumab an ideal therapeutic choice for pediatric IBD. However, an important limitation is its delayed onset of action, for which corticosteroid use as bridge therapy is often necessary in this population that is already at increased risk of growth failure and bone loss. Recently, Hamel and colleagues published their small, single-center experience of using concomitant tacrolimus between anti-TNFα withdrawal to vedolizumab maintenance as a corticosteroid-sparing bridge therapy in moderate to severe IBD (Ref: Hamel B, Wu M, Hamel EO, Bass DM, Park KT. Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis. BMJ Open Gastroenterol. 2018;5(1):e000195).

This article addresses therapeutic drug monitoring:

TDM is a key component of managing IBD patients on anti-TNFα therapy. While  reactive TDM of antiTNFα agents has been adopted by societal guidelines, there is an increasing body of literature to support the benefit of proactive TDM, particularly in pediatric populations

Conclusions from authors: Anti-TNFα agents have revolutionized the management of IBD, positively modifying the natural disease history in children. Importantly, inception cohort studies of pediatric CD and UC (RISK and PROTECT, respectively) have highlighted the variable course of disease and necessity of adopting an individualized approach with early use of biologic therapy in patients at risk of severe disease progression. 

Biologics Used in Pediatric Inflammatory Bowel Disease

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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

 

Ustekinumab Over Vedolizumab as 2nd Line Agent for Crohn’s Disease

A recent study: Ustekinumab is associated with superior effectiveness
outcomes compared to vedolizumab in Crohn’s disease patients with prior failure to anti-TNF treatment. VBC Biemans et al. Aliment Pharmacol Ther 2020; 52: 123-134.  Thanks to Ben Gold for this reference.

Methods: Crohn´s disease patients, who failed anti-TNF treatment and started
vedolizumab or ustekinumab in standard care as second-line biological, were
identified in the observational prospective Dutch Initiative on Crohn and
Colitis Registry.  128 vedolizumab- and 85 ustekinumab-treated patients fulfilled
the inclusion criteria. Median age in the cohorts were 37 and 39 respectively.

Key findings (at 52 weeks):

  • After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014).
  • Safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups

My take: This study indicates that ustekinumab is likely a more effective 2nd line agent for Crohn’s disease.

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Dose Escalation of Ustekinumab & Support Tool “Should I Have IBD Surgery?”

A recent large retrospective study (Effectiveness of Ustekinumab Dose Escalation in Patients with Crohn’s Disease. JE Ollech, et al. Clinical Gastroenterology and Hepatology, EPUB) shows that increasing the frequency of ustekinumab from every 8 weeks to every 4 weeks improves outcomes in those who are not responding optimally. Among 506 patients receiving ustekinumab, 110 had dose escalation.

From abstract:

Results

Following dose interval shortening, the patients’ median HBI [Harvey Bradshaw index] decreased from 4.5 to 3 (P=.002), the median level of CRP decreased from 8 mg/l to 3 mg/l (P=.031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P=.57). Among patients who had an HBI >4, a level of CRP ≥5mg/dl, a level of fecal calprotectin >250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (<5 mg/dl), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission.

My take (borrowed from authors): “Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe.”

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From ImproveCareNow: Should I Have Surgery? A Shared Decision Making Tool  –Recommended for families in working through this difficult treatment decision.

Tiny door on the Atlanta Beltline

Pipeline Medications for Ulcerative Colitis (Part 2)

To continue with topic of new medications for ulcerative colitis started yesterday -two more articles:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 537-49
  • S Danese. Gastroenterol 2020; 158: 467-70 (commentary)

The first reference describes a randomized phase 2 study of mirikizumab with 249 patients.  Mirikizumab is a monoclonal antibody to the p19 subunit of IL23. A similar agent, ustekinumab is a monoclonal antibody directed at the p40 subunit of IL23 and IL12; thus mirikuzumab is more selective targeting of IL23. the authors examined response to the study drug at 3 doses: 50 mg, 200 mg, and 600 mg and compared to intravenous placebo.  All patients received dosing at weeks 0, 4, and 8. A subset of patients continued with subcutaneous treatment starting at week 12, with 47 receiving 200 mg every 4 weeks and 46 receiving 200 mg every 12 weeks. 63% of patients in this trial had previous exposure to biologics.

Key findings:

  • At week 12, 15.9% (50 mg), 22.6% (200 mg), and 11.5 % (600 mg) in the treatment groups achieved clinical remission compared to 4.8% of the placebo group
  • Clinical responses occurred in 41.3%, 59.7%, and 49.2% in the respective treatment groups compared to 20.6% in placebo group
  • At week 52, clinical remission was achieved in 46.8% of SC every 4 weeks and 37.0% every 12 weeks.

In the commentary, Danese reviews the pipeline of new drugs emerging for ulcerative colitis.  Full Text Link: New Drugs in the Ulcerative Colitis Pipeline: Prometheus Unbound

A couple of key points:

  • “Like Prometheus, who gave fire to humans and paid with the price of eternal torment, so the gift of new drugs in ulcerative colitis brings the consequence of patients with heterogeneous disease being cycled indiscriminately through similarly modestly effective agents.”
  • “Predictive biomarkers are needed” to optimize treatment and avoid ineffective and potentially harmful treatments

My take: The emergence of new treatments is welcome given the frequent loss of response or lack of response to current therapies.  Two questions: How will we decide which agent(s) is the best one to use? When will pediatric studies be available?

 

 

IBD Shorts March 2020

Ustekinumab Predictor. At recent ACG meeting, PS Dulai presented data on 781 adult patients that was used to determine likelihood of ustekinumab response. Source: GIHepNews: New ustekinumab response predictor in Crohn’s called ‘brilliant’

Variable  & Points:

  • No prior anti-TNF agents:  2 points
  • No prior bowel surgery: 2 points
  • No smoking (current or prior): 1 point
  • No active fistulas: 1 point
  • Baseline albumin: >4.3    3 points, >3.9-4.3     2 points, >.3.2-3.9   0 points,     >2.5-3.2    -1 point, 2.5 or less   -3 points

Probability of Response Interpretation:

  • High if ≥5 points
  • Intermediate if 2-4 points
  • Low if 0 or 1 points

Infliximab outperformed golimumab for moderate-to-severe ulcerative colitis. S Singh et al. Clin Gastroenterol Hepatol 2020; 18: 424-31. Using data from three phase 3 trials (1793 patients), the authors found that infliximab worked more rapidly and with greater efficacy than golimumab.  At week 6, patient reported outcome of clinical remission was 50.0% and 38.9% (aOR 2.0).  After adjusting for patient variables, infliximab was superior in achieving clinical remission with aOR 3.01 (39% vs. 21%).

Increasing incidence of inflammatory bowel disease in Latin America and Caribbean. PG Kotze et al. Clin Gastroenterol Hepatol 2020; 18: 304-12. This systematic review examined incidence & prevalence of IBD over the last 30 years. In Brazil, for example, the incidence of Crohn’s disease jumped from 0.08 per 100,000 person-years in 1988 to 5.5 per 100,000 person-years in 2015.

IBD Passport Website: IBD Passport homepage. “IBD Passport is an award winning website that aims to provide comprehensive, practical and reliable information on all aspects of travelling with Crohn’s Disease or Ulcerative Colitis (Inflammatory Bowel Disease). IBD Passport is the first website to combine this information into one resource to make planning your trip easy. IBD Passport is a UK registered non-profit charity (Registered number: 1171268) with a global reach aimed to support IBD travellers of all nations and regions in the world.”

Adverse Effects of Low-Dose Methotrexate (≤20 mg/week). DH Solomon et al. Ann Intern Med. 2020. DOI: 10.7326/M19-3369. n=4786, median age 66 years. This was a secondary analyses of a double-blind, placebo-controlled, randomized trial. “With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs.” There were increased risks of gastrointestinal, infectious, pulmonary, and hematologic AE.

 

 

 

Most Popular Posts of 2019

The following are the most viewed posts from the past year:

Wishing friends, family and colleagues a healthy and happy New Year.

Morning in Sandy Springs, GA

 

#NASPGHAN19 Postgraduate Course (Part 5)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course.  There may be errors in omission or transcription on my part.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

– Intestinal Inflammation Session

192 David T. Rubin, MD, University of Chicago Positioning the new IBD therapies: Merging experience with evidence

Some key points:

  • Ustekinumab escalation can increase response. Optimization in CD patients with loss of response led to recapture of response in 69% of patients
  • Tofacitinib –given black warning, will likely be used in more refractory patients
  • May be able retry a previous therapy (Chicago protocol in slide below)

As an aside, while Dr. Rubin is an excellent speaker, my view is that there are so many terrific pediatric IBD specialists, I would favor having a pediatric IBD specialist give this talk at our postgraduate course.  (Some might argue that adult IBD specialists would have more experience with emerging therapies.)

204 Anne Griffiths, MD, FRCPC, Hospital for Sick Children Immunosuppressive therapy in IBD: Can we de-escalate therapy?

  • High rate of relapse when biologic therapy is stopped.  Use of an immunomodulator may reduce the relapse rate when stopping an anti-TNF agent

215 Stacy Kahn, MD, Boston Children’s Hospital When it is not IBD … rare forms of intestinal inflammation

  • For patients with milder microscopic colitis, antidiarrheal agents can be given.  For more severe disease, budesonide is effective.

223 Edaire Cheng, MD, UT Southwestern Medical Center  Eosinophilic inflammation beyond the esophagus

 

Disclaimer: NASPGHAN/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. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society 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. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

Ustekinumab for Ulcerative Colitis (UNIFI Trial)

A landmark study (BE Sands et al. NEJM 2019; 381: 1201-14) shows that ustekinumab (Stelara) can be an effective therapy for moderate-to-severe ulcerative colitis (UC); it is already an approved, established therapy for Crohn’s disease. This randomized placebo-controlled study included an 8-week induction trial (n=961) followed by a 44-week maintenance trial (n=523) for patients with response.

Clinical remission was defined as a total socre of ≤2 on the Mayo scale (range 0-12) and no subscore >11 on any of the four Mayo scale components.

Key findings:

  • During induction, there was a similar clinical remission rate between those who received 130 mg fixed intravenous dose compared to those who received 6 mg/kg: 15.6% and 15.5% compared to 5.3% for placebo group.
  • During maintenance, among patients receiving 90 mg every 8 weeks the clinical remission rate at 44 weeks was 43.8%, in those with 90 mg every 12 weeks the rate was 38.4%; placebo group was 24.0%.
  • The response to ustekinumab occurred in those with or without previous treatment failure with biologic agents, though response was lower in both induction and maintenance in those with prior treatment failure.  In both phases, at least 59% of participants had failed either or both anti-TNF agents or vedolizumab.
  • In this study, there were similar serious adverse events with ustekinumab compared to placebo.  In the treatment groups, there were two deaths (one from ARDS, one from esophageal varices) and 7 cases of cancer (3 nonmelanoma skin cancer, two colon cancer, one prostate, one renal).  There was one death from testicular cancer in the placebo group. Also four patients in the ustekinumab group had opportunistic infections including CMV in two, legionella in one and HSV in one.

In terms of dosing, the authors note that there was greater improvement in calprotectin values during induction in the group who received 6 mg/kg compared to those who received 130 mg.  At week 44, using more objective and stringent end points (eg. endoscopic improvement), greater clinical benefit was observed with the every 8 week regimen.

Visual abstract from NEJM Twitter Feed:

The following image depicts patients response during the maintenance phase –the lightest color is placebo, followed by every 8 weeks, and then the darkest color is every 12 weeks.  The x-axis measures (left to right) are clinical remission, maintenance of clinical response at week 44, endoscopic improvement, corticosteroid-free remission, and remission at 44 weeks in those with remission after induction.

My take: Ustekinumab is more effective for placebo in patients with ulcerative colitis.  More experience is needed to understand its long-term safety.

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