SEAVUE: Head-to-Head Ustekimumab vs. Adalimumab

BE Sands et al.Lancet 2022; 399: 2200-2211. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial

Methods: This was  “a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn’s…Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications.”

386 patients were enrolled.

Key findings:

  • 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52
  • At week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (CDAI <150)
  • Endoscopic remission at week 52: ustekinumab 29% and for adalimumab 29%
  • Endoscopic response at week 52: ustekinumab 42%and for adalimumab 37%
  • Rapid onset of clinical response was seen with both therapies with improvement noted as early as week 2 assessment
  • Antidrug antibodies were less frequent with ustekinumab compared to adalimumab: 2% vs 74%.
  • Infections were reported in 65 (34%) of ustekinumab group compared to 79 (41%) of adalimumab group. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group.
  • No deaths occurred through week 52 of the study.

My take:

  1. Both medications had a high similar response rate. Ustekinumab had fewer patients discontinue medication and lower immunogenicity which could improve efficacy/duration of response in an extended study.
  2. It is good to see a well-designed head-to-head study rather than a placebo-control arm. Placebo-based studies are hard to justify given the availability of multiple effective agents.

Near Denali, AK

Head-to-Head (Sort of): Infliximab vs Ustekinumab for Crohn’s Disease

N Narula et al. Clin Gastroenterol Hepatol 2022; 20: 1579-1587. Comparative Efficacy and Rapidity of Action for Infliximab vs Ustekinumab in Biologic Naïve Crohn’s Disease

Using a post hoc analysis of 2 large Crohn’s disease (CD) trial with 420 biologic-naive adult patients, the authors found the following Key Findings:

  • At week 6, a comparable number of patients achieved clinical remission with infliximab compared with patients treated with ustekinumab (44.9% vs 37.9%; adjusted odds ratio [aOR], 1.22)
  • At week 6 the clinical response rates were not significantly different (58.4% infliximab vs 54.9% ustekinumab; aOR, 1.25)
  • At week 6, 42.3% infliximab vs 34.7% ustekinumab had fecal calprotectin level less than 250 mcg/L in those with increased values at baseline

My take: A true head-to-head trial, rather than a post-hoc analysis, would more definitively determine relative efficacy and relative time to response. This study indicates that both agents have similar efficacy by week 6.

Related blog posts:

Fountain at Forsyth Park in Savannah

Can You Give Ustekinumab Subcutaneously After IV Reaction?

J Sunny et al. JPGN Reports: May 2022 – Volume 3 – Issue 2 – p e205 Open Access: Hypersensitivity Reaction to Ustekinumab in Pediatric and Young Adult Inflammatory Bowel Disease Patients: A Case Series

This is a case series of six pediatric patients and young adults who developed hypersensitivity reactions during intravenous infusion with ustekinumab (UST).

Key findings:

  • Hypersensitivity reactions during intravenous (IV) induction dose of UST, ranging from mild allergic reactions to anaphylaxis, with no antibodies detected in the two who had testing
  • Reactions occurred 0-30 minutes after start of infusion
  • Management was with methylprednisolone in 5 of 6 patients, diphendyramine in 3 of 6, and epinephrine in 1. One patient was managed with IV diphenhydramine alone.
  • Four of six continued with UST subcutaneously without reactions. ***Change of formulation of UST from IV to subcutaneous was done in a controlled hospital-based setting. The other two 33% were switched to another biologic due to physician preference and were never exposed to the subcutaneous formulation
  • Although the exact pathogenesis of this infusion reaction remains unknown, it has been attributed to EDTA

My take: It appears that patients with UST hypersensitivity reactions can be changed to SC formulation. The authors recommend to trial a subcutaneous dose of UST in a controlled setting; in addition, they suggest testing with skin prick testing or specific IgE levels to EDTA done by allergy and immunology.

Related blog posts:

Sandia Mountain, near Albuquerque

IBD Shorts: Ustekinumab in Kids, Subcutaenous Infliximab, Nutrition Highlights

MT Dolinger et al. J Crohns Colitis 2022.  doi: 10.1093/ecco-jcc/jjac055. Online ahead of print. Outcomes of Children With Inflammatory Bowel Disease Who Develop Anti-Tumor Necrosis Factor Induced Skin Reactions

In this retrospective study, among those who developed skin reactions to anti-TNF agents, 71 (64%) continued anti-TNF and 40 (36%) switched to ustekinumab (UST). Key findings:

  • Switching to UST had a higher rate and odds of resolution of skin findings (29/40 (73%) vs. 24/71 (34%); p <0.0001) and combined remission (21 (52%) vs. 22 (31%); p=0.03) vs. continuing anti-TNF at 6 months

PJ Smith et al. J Crohns Colitis, jjac053, https://doi.org/10.1093/ecco-jcc/jjac053 Open Access: Efficacy and Safety of Elective Switching From Intravenous to Subcutaneous Infliximab (Ct-P13): A Multi-Centre Cohort Study

Patients (n=181) on established maintenance IV infliximab who switched to SC CT-P13 were included in this retrospective multi-centre cohort study. Key findings:

  • Treatment persistence rate was high (N=167, 92.3%) and only 14 patients (7.7%) stopped treatment during the follow-up period. There were low rates of immunogenicity with no change in clinical disease activity indices or biomarkers

Link: Crohn’s and Colitis Congress 2022 Nutritional Highlights (Nutritional Therapy for IBD Website). This website has a summaries, and links to extensive information (videos/posters) from recent IBD meeting.

Sunrise in Sandy Springs (4/9/22) -no filter

Ustekinumab vs Adalimumab: Head-to-Head Study

From Gastroenterology & Endoscopy News: Head-to-Head Trial Shows Similar Efficacy and Safety With Ustekinumab and Adalimumab

An excerpt:

The first head-to-head trial comparing ustekinumab and adalimumab has found the two drugs are similarly safe and effective in patients with moderate to severe Crohn’s disease

Dr. Scherl and her co-investigators in the SEAVUE trial randomly assigned 386 biologic-naive patients with Crohn’s disease to receive one year of treatment with either ustekinumab or adalimumab at standard on-label doses, with no dose escalation throughout the study period and no concomitant immunomodulators...

The findings, which were presented at the 2021 annual meeting of the European Crohn’s and Colitis Organisation (oral presentation OP02), showed that after one year of treatment, 65% of patients who received ustekinumab and 61% of those who received adalimumab achieved clinical remission, defined as a CDAI below 150...[And] similar additional outcomes, including clinical response at one year (72.3% for ustekinumab vs. 66.2% for adalimumab), corticosteroid-free remission at one year (60.7% vs. 57.4%, respectively), endoscopic remission at one year (28.5% vs. 30.7%) 

My take: This study indicates that ustekinumab likely has similar safety and efficacy as adalimumab (though the study did not allow dose escalation or immunomodulators); thus, it could be positioned as a first-line treatment. It is administered less frequently as well.

Related blog posts:

Ustekinumab in Pediatric Patients and More on VTE Prophylaxis

FS Kim et al. JPGN 2021; 73: 610-614. Open Access (PDF): Experience Using Ustekinumab in Pediatric Patients With Medically Refractory Crohn Disease

In this retrospective study with 38 pediatric patients with Crohn’s disease, 34% had stricturing or penetrating disease. Key findings:

  • At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1 weeks, and 60.5% achieved clinical remission
  • 89.5% of patients had no significant adverse events
  • Sixteen (of 38, 42.1%) patients required dose escalation, to every 4 weeks (n= 15 of these 16, 93.8%) or every 6 weeks (Nn=1 of 16, 6.3%)

My take: Ustekinumab had good efficacy in this group of refractory pediatric patients.

Related blog posts:

E Story et al. JPGN 2021; 73: 604-609. Safety of Venous Thromboprophylaxis With Low-molecular-weight Heparin in Children With Ulcerative Colitis

In this retrospective study with 218 inpatient pediatric patients with active ulcerative colitis, the key findings:

  • Use of enoxaparin did not result in a greater fall in hemoglobin among those with acute severe colitis (initial PUCAI ≥65) during the week following admission and there was not an increased risk of needing a transfusion
  • VTE occurred in 2 of 130 in control group and 1 of 88 in enoxaparin group (enoxaparin group was sicker)

My take: The absolute risk of VTE is low in the pediatric population. This study shows that enoxaparin prophylaxis is NOT associated with increased issues with blood loss. In those with active disease, the presence of CVC and use of steroids are known risk factors and require consideration of, at minimum, nonpharmacologic interventions.

Related blog posts:

Billy Goat Trail, Chesapeake and Ohio Canal National Park

Encouraging Safety Data for Ustekinumab & ESPGHAN Obesity Position Paper

WJ Sandborn et al. Inflamm Bowel Dis 2021; 27: 994-1007. Full text: Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year; this included 2574 patients (1733 patient-years of follow-up)

Key Safety findings –Events per 100 patient years -placebo vs ustekinumab respectively:

  • Adverse events: 165.99 [95% CI, 155.81–176.67] vs 118.32 [95% CI, 113.25–123.55])
  • Serious AEs: 27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51])
  • Infections 80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21])
  • Serious infections: 5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19])
  • Malignancies excluding nonmelanoma skin cancer: 0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83])
  • Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12

More key findings:

  • No cases of progressive multifocal leukoencephalopathy or reversible posterior leukoencephalopathy
  • Antibodies to ustekinumab were identified in 3.6% of patients

My take: This study showed similar safety between ustekinumab and placebo, but is limited by short followup. The authors note that 5-year data from ustekinumab’s use with psoriasis has found no safety signals for malignancy.

Related blog posts:

Unrelated article: E Verduci et al. JPGN 2021; 72: 769-783: Full text: Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition

Why I Didn’t Like a Study on Resilience Plus One

P Sehgal et al. Inflamm Bowel Dis 2021; 27: 791-796. High Levels of Psychological Resilience Associated With Less Disease Activity, Better Quality of Life, and Fewer Surgeries in Inflammatory Bowel Disease

This cross-sectional study with 229 patients examined the relationship between inflammatory bowel disease (IBD) activity and resilience based on the Connor-Davidson Resilience Scale questionnaire (high resilience score ≥ 35).

Key findings:

  • High resilience was noted in 27% of patients with UC and 21.5% of patients with CD.
  • Among patients with UC, those with high resilience had a mean Mayo score of 1.54, and those with low resilience had a mean Mayo score of 4.31, P < 0.001.
  • Among patients with CD, those with high resilience had a mean HBI of 2.31, and those with low resilience had a mean HBI of 3.95, P = 0.035.
  • In multivariable analysis, high resilience was independently associated with lower disease activity in both UC (P < 0.001) and CD (P = 0.037) and with higher QoL (P = 0.016).
  • High resilience was also associated with fewer surgeries (P = 0.001) among patients with CD.

Reading this study, made me think of Galen’s assertion about a different treatment, circa 100 AD:   “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.” In the case of this study, the remedy is resiliency.

This study is intriguing and adds to the literature that mental health and IBD may be a two-way street: mental health may affect IBD and IBD activity may affect mental health. However, it is difficult to prove causation in a cross-sectional study. Reverse causation is possible; that is higher disease burden may result in lower resilience.

Also, it is not clear to me that resilience is a particularly modifiable factor. Some may interpret this study in a ‘blame the victim’ mode. I think a lot of individuals would think they are resilient but most do not know until they face a difficult situation. Perhaps, Mike Tyson’s assertion is more apt: “Everyone has a plan until they get punched in the mouth.”

My take: This study does not prove that resilience helps prevent IBD activity, though being resilient is nice if you have it.

Plus one: JR Rosh et al. J Crohns Colitis. 2021 May 26; jjab089. doi: 10.1093/ecco-jcc/jjab089. (EPUB). Ustekinumab in Pediatric Patients with Moderately to Severely Active Crohn’s Disease Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study This was a “multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108), patients aged 2-<18 years; patients were randomized (1:1) to one of 2 weight range-based intravenous induction doses: 130mg vs 390mg in patients ≥40kg and 3mg/kg vs 9mg/kg in patients <40kg. At week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90mg in patients ≥40kg or 2mg/kg in patients <40kg..” (Kudos to my partner, Stanley Cohen, one of the authors)

Key finding:  Pharmacokinetics were similar to those in adults with Crohn’s disease. However, serum ustekinumab concentrations were lower among those with body weight <40kg…These results suggest a different dosing regimen may be required for patients <40kg

Related blog posts:

Image below from Anne’s Beach (Lower Matecumbe Key, Florida)

2021 AGA Guidelines For Crohn’s Disease

A series of articles details the 2021 AGA Guidelines for Crohn’s disease (CD) including a clinical practice guideline (pg 2496-2508), a clinical decision support tool (2509-2510), a spotlight summary (pg 2511), a technical review (2512-2557), and a review of the recommendations (pg 2557-2262). I will highlight the first article.

JD Feuerstein et al. Gastroenterol 2021; 160: 2496-2508. Full text: AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

Full text: Spotlight

For me the most important of their recommendations was #7:

  • In adult outpatients with moderate to severe CD, the AGA suggests early introduction with a biologic with or without an immunomodulator rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.

Other points:

From Spotlight:

Ustekinumab for Refractory Pediatric Ulcerative Colitis and Updated Adalimumab Dosing

As noted in previous blog posts (see below), adult guidelines for ulcerative colitis favor ustekinumab over vedolizumab for ulcerative colitis patients who have had anti-TNF therapy; recent pediatric guidelines appeared to do the opposite, possibly due to limited data with ustekinumab.

A recent study (J Dhaliwal et al. AP&T 2021; https://doi.org/10.1111/apt.16388. One‐year outcomes with ustekinumab therapy in infliximab‐refractory paediatric ulcerative colitis: a multicentre prospective study) provides prospective data on ustekinumab effectiveness when given to children with UC refractory to other biologics; n=25. Thanks to Ben Gold for this reference.

Key findings:

  •  All patients had failed prior infliximab therapy, and 12 (48%) also had failed vedolizumab.  Five patients discontinued ustekinumab after IV induction (four undergoing colectomy).
  • On intent to treat basis, 44% (n=11) achieved the primary endpoint of steroid‐free remission at week 52, including nine (69%) of 13 who previously treated with anti‐TNF only vs two (17%) of 12 who previously failed also by vedolizumab. Seven of 11 remitters met the criteria for endoscopic improvement.
  • Higher trough levels were not associated with a superior rate of clinical remission; the median (IQR) trough levels (μg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6‐9.9] vs 3.8 [12.7‐4.8]) P = 0.02.
  • No adverse events were associated with therapy.

My take: Ustekinumab is a good option for pediatric patients with ulcerative colitis who are refractory to anti-TNF agents. More data are needed to help in positioning therapies.

Also, Humira (adalimumab) is now FDA-approved for children as young as 5 years with ulcerative colitis: FDA Approves Adalimumab as Treatment for Children With Ulcerative Colitis (2/25/21). “This approval is based on results from the phase 3, randomized, double-blind, multicenter ENVISION I (NCT02065557) study.” Abbvie has now updated their Humira dosing recommendations (Reference:  https://www.rxabbvie.com/pdf/humira.pdf). Thanks to Clair Talmadge for this update.

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