Tag Archives: ustekinumab

Dr. Maria Oliva-Hemker: Positioning Therapies for Pediatric Crohn’s Disease

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Recently, Dr. Maria Oliva-Hemker gave our group an excellent update on Crohn’s disease therapies.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

Key points:

  • Early advanced therapy results in better outcomes (see The PROFILE study results below as one example)
  • Anti-TNFs are the only therapy with a specific FDA pediatric indication. Medications can take 8-10 years after use in adults for pediatric labeling
  • IL-23 specific agents (like risankizumab) are more effective than ustekinumab that target both IL-23/IL-12
  • Recent studies show that ustekinumab is effective in children. Also, in patients who respond to ustekinumab, there is good durability
  • Infliximab is a top-line therapy in Crohn’s disease
  • Risankizumab is a top-line therapy in both biologic-naive and biologic-exposed patients with Crohn’s disease. Higher maintenance doses may capture more patients.
  • Upadacitinib is a very good therapy in patients with prior advanced therapies with either Crohn’s or ulcerative colitis. It also has a rapid onset of action (within 2 weeks)
  • Vedolizumab is less effective in those who are biologic-exposed. However, patients with predominantly colonic (UC-like) involvement may be better-suited for this therapy
  • Close monitoring and treat-to-target approaches are recommended. Usually followup scope is undertaken after one year (&/or one year after switching therapy)
  • Combination advanced therapies have shown effectiveness but it is unclear which combinations are optimal
This slide shows the Montreal Classification, an organ-based phenotype, to describe the anatomic extent and behaviors of Crohn’s disease;. The figure on the right illustrates extraintestinal manifestations of IBD. It is expected that disease classification will rely more on a molecular based approach.
The STRIDE project which defined goals of treatment was the result of consensus achieved by the International Organization of IBD. The first recommendations came out in 2015 and then these were updated in 2021 to incorporate a pediatric component.
The PROFILE study with 386 adults showed how important early effective advanced therapies. Patients receiving infliximab/azathioprine within a median of 15 days from diagnosis had remarkably better outcomes compared to step up treatment with prednisone + azathioprine.
The cytokine IL12 and IL23 shown as circles with 2 subunits attaching to their receptors share a p40 subunit (shown in red). Ustekinumab binds to that p40 subunit thereby inhibiting both the IL12 and IL23 pathways. IL23 inhibitor. Risankizumab, Mirkizumab, Guselkumab inhibit only the p19 subunit (shown in blue) and so  they only downregulate the IL-23 pathway.
Jak inhibitors targets are intracellular in location.
Pediatric data: Multicenter 2015-2020; primary outcome was CS-free remission after 1 yr. Prior to use, 50% failed 1 anti TNF and 30% 2 anti TNF. At one year, 59/101 were in steroid free remission
Upadactinib studies: Oral induction dose for UC and CD is 45 mg daily for induction
and with reduction in maintenance to 30 mg or 15 mg
Due to limited head-to-head studies, network meta analyses provides indirect evidence of comparative effectiveness. It relies on how effective a medication was compared to placebo. One of the problems with these comparisons is that there are different populations in each of these studies.
In patients who need speed to reduce symptoms, upadacitinib is favored over IL-23 agents

Though Dr. Oliva-Hemker’s lecture did not focus on ulcerative colitis, she did note that their center has recommended frequent colonoscopies (often yearly) in many of their patients with the combination of ulcerative colitis and PSC. This is due cases of colon cancer in their pediatric cohort.

Related blog posts:

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.

Crohn’s Disease: Risankizumab Real-World Data

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A Zinger et al. Clin Gastroenterol Hepatol 2024; 22: 1336-1338. Risankizumab Effectiveness and Safety in Crohn’s Disease: Real-world Data From a Large Tertiary Center

In a group of 80 patients with Crohn’s disease with evidence of active disease, the authors examined the effectiveness of risankizumab with prospectively-collected data. Patients received 600 mg intravenously at 0, 4, and 8 weeks. Only 6 patients (8%) were unexposed to prior advanced therapy; 44 patients (55%) had prior ustekinumab (UST) therapy.

Key findings:

  • Clinical remission was 78% in patients without prior ustekinumab therapy and 64% in those with prior ustekinumab therapy
  • Steroid-free clinical remission was 75% and 52%, respectively in patients without and with prior ustekinumab therapy. Overall, 63% of patients achieved a steroid-free clinical remission

My take: This study shows that risankizumab, a selective IL23 inhibitor, has good effectiveness, even in patients previously treated with a IL12/23 inhibitor. It highlights our need to better understand the reasons why a more selective agent is able to work after patients failed to respond to UST treatment.

Unrelated article: KA Chien et al. JPGN 2024; 79: 10-17. (Kudos to the authors including my partner Dr. Ben Gold). This article detailed the median work RVUs target for practices and composition of healthcare team to provider ratios: Nursing 0.80, MA 0.29, dietician 0.29, social worker 0.14, and psychologist 0.13. The article reviews salary structure/incentives and wellness initiatives as well.

Related blog posts:

IBD Updates: Reducing Postoperative Crohn’s Disease, How Effective is IFX after Adalimumab, UST vs VDZ in Pediatric UC

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C Hernandez-Rocha et al. J Crohns Colitis 2024: 18: 615–627. Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn’s Disease

Prospective Study n=365 adult patients with post-operative Crohn’s disease. Findings: At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95), non-White ethnicity [OR = 2.48], and postoperative smoking [OR = 2.78] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43]

A Lecoutour et al JPGN 2024; 78:1116–1125. Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn’s disease: A retrospective multicenter cohort study of the “GETAID pédiatrique”

Key findings: In this retrospective study, 27 of 32 patients (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At 1 year, 22 patients were in corticosteroid free clinical remission (68.7%).

PV Patel et al. JPGN 2024; 78:1126–1134. Real‐world effectiveness of ustekinumab and vedolizumab in TNF‐exposed pediatric patients with ulcerative colitis

Using the ICN registry, this observational study had 262 anti-TNF refractory patients receiving VDZ and 74 patients receiving UST. Key finding: At 6 months, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p= 0.76)

Orchid, Atlanta Botanical Gardens

Tofacitinib vs Ustekinumab -Which is Better for Ulcerative Colitis?

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RS Dalal et al. Inflammatory Bowel Diseases, Volume 30, Issue 3, March 2024, Pages 395–401. 1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure

In this real-world cohort of anti-TNF-exposed patients with ulcerative colitis, tofacitinib (n=69) and ustekinumab (n=97) demonstrated similar effectiveness in achieving steroid-free clinical remission (SCFR) at 12 and 52 weeks. The median follow-up was 88.0 and 62.0 week, respectively. 35 of 66 in the tofacitinib cohort had dose reduction from the starting dose of 10 mg twice daily. This reduction occurred at a mean of 144 days. 59 of 97 in the ustekinumab cohort received either Q4W dosing (n=43) or Q6W (n=16).

Key findings:

  • 53% of patients receiving tofacitinib and 32% of patients receiving ustekinumab achieved SFCR at 12 weeks. Tofacitinib-treated patients had higher baseline Mayo endoscopic subscores and CRPs.
  • At 52 weeks, approximately 50% of patients in both treatment groups achieved SFCR. There were also high proportions (>60%) of patients in both treatment groups who had endoscopic response within 52 weeks.
  • Both drugs were well-tolerated, as only 1 patient in each treatment group discontinued therapy due to an AE during >260 patient-years of follow-up.

My take: This shows similar response to either tofacitinib and ustekinumab in a cohort that had refractory disease as patients were anti-TNF failures and most had prior vedolizumab as well.

Related blog posts:

IBD Updates: Newer biologics for post-op Crohn’s, Vedolizumab-exposed newborns, and Anti-TNF injections for Orofacial Granulomatosis

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FH Mourad et al. Inflammatory Bowel Diseases, Volume 30, Issue 3, March 2024, Pages 459–469. Open Access! Are the New Biologics Effective in the Management of Postoperative Crohn’s Disease?

In this  a systematic review, the authors identified 32 relevant studies. The literature review revealed some encouraging, although conflicting, results on the role of the newer biologic agents, ustekinumab and vedolizumab, in the prevention and treatment of postoperative Crohn’s disease. My take: More high-quality studies are needed to determine the effectiveness of these newer biologics at preventing recurrence disease activity after resection.

This is their recommended management algorithm:

 ¥Other factors to consider are duration of Crohn’s disease,
age of patient at diagnosis, and length of stricture.

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JH Gorodensky et al. Inflammatory Bowel Diseases, Volume 30, Issue 3, March 2024, Pages 496–498. Serious Infections in Offspring Exposed in Utero to Vedolizumab

Background/Methods:  “Offspring exposed to vedolizumab in utero are born with lower blood drug (relative to maternal drug levels) compared with offspring exposed to TNFi or ustekinumab.4,5 In addition, offspring exposed to vedolizumab are known to clear the drug quickly after birth.6” In this IBM MarketScan database cohort of 8507 offspring to women with IBD, 43 offspring were exposed to vedolizumab. Key findings:

Key finding: The cumulative incidence of serious infection at 1 year was 2.3% in the vedolizumab group. This was lower than in those who had no drug exposure (3.0%) and similar to the rate in the TNFi (2.9%), traditional immunosuppressants (2.5%), and groups. Discussion: “This aligns with data from the PIANO study,5 a French retrospective cohort study,8 and the pan-European CONCEIVE study9“

My take: This article title is textbook clickbait. A more accurate title would be “Lack of Serious Infections in Offspring Exposed in Utero to Vedolizumab”

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J Lee et al. Inflammatory Bowel Diseases, Volume 30, Issue 3, March 2024, Pages 499–500. Intralesional Injections of a TNF-α Inhibitor to Treat Orofacial Granulomatosis

This case report demonstrated successful injection of orofacial granulomatosis in a 24 yo with moderate-to-severe CD of the small and large intestines who presented with facial edema, painful lip sores with crusting, and tongue fissures. After numerous other failed treatments (topical steroids, adalimumab, hydroxychloroquine, prednisone, and methotrexate), the patient who had a mild treatment response to certolizumab had three injections split between thigh and lower lip (intralesional). After improvement, the patient continued to maintain response with injections into the thigh.

My take: This is an interesting case report; however, this is not an established therapy for orofacial granulomatosis.

Is Risankizumab More Effective for Crohn’s Disease Than Ustekinumab?

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M Dubinsky et al. Adv Ther. 2023; 40(9): 3896–3911. Open Access! Matching-Adjusted Indirect Comparison Between Risankizumab and Ustekinumab for Induction and Maintenance Treatment of Moderately to Severely Active Crohn’s Disease

Background/Methods: Risankizumab (RZB) and ustekinumab (UST), interleukin (IL)-23 and IL-12/23 inhibitors, respectively, are approved treatments for moderately to severely active Crohn’s disease (CD); direct comparison between the two is ongoing. The authors indirectly compared efficacy of RZB versus UST using data from phase 3 trials (three trials for each medication):

Key findings:

Induction: Higher proportions of patients achieved clinical and endoscopic outcomes with RZB vs. UST, resulting in significantly (p ≤ 0.05) greater percent differences between groups for CDAI remission (15%) and endoscopic response (26%) and remission (9%)

Rates of response and remission following induction therapy with RZB (600 mg) or UST (6 mg/kg). *p ≤ 0.05 for RZB versus UST. Relative effect measures are shown as the percent difference between treatment groups; absolute effect measures are the proportions of patients achieving each outcome in each treatment group. BF biologic failure, CCF conventional care failure, CDAI Crohn’s Disease Activity Index, IV intravenous, PBO placebo, RZB risankizumab, UST ustekinumab

Maintenance: rates of CDAI remission were similar (range − 0.3% to − 5.0%) for RZB vs. UST; however, endoscopic response and remission rates appeared more favorable (see Figure 2 below)

Rates of response and remission following maintenance therapy with RZB (180 mg or 360 mg) or UST (90 mg Q8W). *p ≤ 0.05 for RZB versus UST. Relative effect measures are shown as the percent difference between treatment groups; absolute effect measures are the proportions of patients achieving each outcome in each treatment group. BF biologic failure, CCF conventional care failure, CDAI Crohn’s Disease Activity Index, PBO placebo, Q8W every 8 weeks, Q12W every 12 weeks, RZB risankizumab, SC subcutaneous, UST ustekinumab

My take: Since this was not a direct randomization trial, these results are not definitive. However, in this indirect analysis, risankizumab appears to be superior to utekinumab in effectiveness of for Crohn’s disease.

Related blog posts:

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.

How Much Ustekinumab (Stelara) Is Needed to Get a Good Response

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K Chen et al. Inflamm Bowel Dis 2023; 29: 1499-1503. Serum Ustekinumab Concentrations Are Associated With Improved Outcomes With the Magnetic Resonance Index of Activity for Crohn’s Disease

This retrospective trial included thirty three patients with Crohn’s disease (CD) receiving maintenance ustekinumab (UST). The simplified Magnetic Resonance Index of Activity (sMARIA) and biomarkers were correlated with UST levels. The authors utilized a homologous mobility shift assay (HMSA) (Prometheus) for their UST levels.

Key findings:

With UST level greater or equal to 8.4, radiologic remission was seen in 63% compared to 21% in those with levels <8.4. Similarly, the absence of severe inflammation was seen in 78.9% of those with higher levels compared with only 36.8% in those with levels below 8.4.
Both findings were clinically-significant P=.01
With UST levels greater or equal to 6.1, FCP less than 50 was seen in 72.2% compared to only 12.5% in those with a level less than 6.1. P<.01

My take: This study show the need for higher levels of UST to achieve optimal outcomes. Levels of at least 8.4 appear to be a good target.

Related blog posts:

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.

CCFA 2023 (Atlanta) Part 2

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There were a bunch useful lectures at CCFA 2023 regional conference in Atlanta. Here are some of my notes and slides from Doug Wolf‘s lecture; my notes may have errors of omission or transcription. Can get access to full slide set (n=37) here: Dose Escalation of Biologic Therapy and Dual Biologic Therapy

  • If loss of response to anti-TNF, consider dose escalation by either re-induction or increasing (doubling) dose. Re-induction is less costly
  • Dose escalation generally not effective for vedolizumab
  • Dose escalation (increased frequency) with ustekinumab can be effective.  Therapeutic drug monitoring can provide guidance.  Re-induction can also be effective in half of patients (especially in patients with either no prior biologics or one prior biologic)
  • Risankizumab can still work in patients who had not responded by 12 weeks (delayed responders)
  • Discussed several combination treatments -no large studies thus far

CCFA 2023 (Atlanta) -Part 1

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I recently attended a regional CCFA conference. David Rubin gave several terrific lectures. Here are some of my notes and some slides from this lecture. My notes may contain transcription errors as well as important omissions. Can get access to full set of slides here: Biologics and Their Biosimilars

“Biologics and Their Biosimilars“

What is a Biologic Therapy?

Dr. Rubin makes a point of explaining the term to patients.  It is a protein made in a living cell that targets another protein.  Term “biologic” can sound scary to patients.  Usually given IV because they cannot be absorbed through the small bowel.

IBD Treatment Revolutions

  • Steroids -overnight changed mortality in IBD
  • Anti-TNF Therapy in IBD -taught many lessons. Treat earlier –>better outcomes. 

Anti-TNF Therapy

  • Frequent loss of response.
  • Earlier treatment with biologics result in better outcomes.
  • Immunogenicity is mainly an issue with anti-TNF agents and not much of an issue with other biologics. Episodic therapy is a big risk factor for anti-drug antibodies. 
  • If staying with in-class medication, after anti-drug antibodies, need to take additional measures to prevent anti-drug antibodies (eg. Immunomodulators).
  • Combination therapy is more effective (SONIC, UC SUCCESS trials).  This is due to using multiple mechanisms of disease control, reduction in anti-drug antibodies, and elevated serum drug levels.
  • Good therapeutic levels appears to deliver similar results as combination therapy
  • Pre-week 6 level of 17 or greater, associated with good response in maintenance.  If level is low, presumption is that higher dosing will be beneficial.
  • Higher levels of infliximab trough levels needed for perianal fistula healing (improved with ciprofloxacin).  Higher levels could be causally-related to healing or could be a marker that there is less inflammation and a patient is responding.
  • Anti-TNFs do not appear to increase risk of infections (see PUCCINI study)

Anti-23 and Anti-IL-12/IL-23

  • Tissue selective targeted therapy –>excellent safety profile
  • IV loading and SC maintenance
  • Excellent for bowel and skin
  • IL-23 is not expressed in joints
  • Ustekinumab is effective for perianal disease and ulcerative colitis
  • Risankizumab is superior to ustekinumab in plaque psoriasis.  If loss of response to ustekinumab, can still respond to Risankizumab

Anti-Integrins:

  • Natalizumab (not used frequently in IBD)
  • Vedolizumab.  Affects mucosa (can explain frequent nasopharyngitis)
  • Vedolizumab -terrific safety profile.  No PML, no malignancy risk

Biosimilars:

  • If biosimilar found effective for one approved condition, extrapolation given to all indications
  • IBD switching studies have NOT shown increased loss of response.  Consider reassess prior to switch to help determine if patient truly in remission prior to switch. Switching often blamed for loss of response when many times the disease was not under good control prior to switch
  • Interchangeable indicates that the drug can be switched by pharmacists
  • Biosimilars are saving insurers money but no proof that this is saving patients money
  • Anti-drug antibodies will cross-react to biosimilars

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.

Comparative Efficacy of Biologics for Crohn’s Disease

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S Singh et al. Clin Gastroenterol Hepatol 2023; 21: 2359-2369. Open Access! Comparative Safety and Effectiveness of Biologic Therapy for Crohn’s Disease: A CA-IBD Cohort Study

There is limited head-to-head data comparing the effectiveness of the biologics used for inflammatory bowel disease. In this study, the authors used a “series of propensity score (PS)-matched cohort studies comparing TNF-α antagonists vs vedolizumab vs ustekinumab in a large, diverse, multicenter, electronic health record (EHR)-based cohort.”

This graphical abstract summarizes the findings, though the first cohort (ustekinumab vs TNFalpha population is actually 1545 not 1030):

Key findings:

  • Ustekinumab-treated patients with CD (n = 515) experienced a lower risk of serious infections (hazard ratio [HR], 0.36), without any difference in the risk of hospitalization (HR, 0.99) or surgery (HR, 1.08) -compared to patients receiving TNF alpha antagonists (n=1030)
  • Ustekinumab-treated patients with CD (n = 221) experienced a lower risk of serious infections (HR, 0.20), without significant differences in risk of hospitalization (HR, 0.76) or surgery (HR, 1.42) -compared to vedolizumab-treated patients (n=221)
  • Compared with TNF-α antagonists (n = 442), vedolizumab-treated patients with CD (n = 221) had a similar risk of serious infections (HR, 1.53), hospitalization (HR, 1.32), and surgery (HR, 0.63).

The increase rate of infections with vedolizumab compared to ustekinumab could be an indication of lower efficacy with vedolizumab as the medication itself has a high safety profile.

In the discussion, the authors comment further on head-to-head studies and lack of these as well. “Biemans et al23 observed that ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (69 patients in each arm, vs vedolizumab; 46.4% vs 29.0%; P = .04) and biochemical remission (42.1% vs 13.2%; P = .01) at 12 months, although these rates were not significant at earlier time points.”

My take: This study provides further evidence that ustekinumab is a good option for Crohn’s disease with regard to both safety and efficacy.

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