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
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)
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.
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.
This post hoc analysis included data from separate trials examined the response of 220 biologic-naïve CD participants to either inflximab biosimilar or ustekinumab.
Key findings:
Clinical remission: One-year clinical remission (CR) and corticosteroid-free CR rates were similar between infliximab-treated and ustekinumab-treated patients (CR, 66 of 110 [60.0%] vs 63 of 110 [57.3%]; adjusted odds ratio [aOR], 1.15), corticosteroid-free CR, 11 of 28 (39.3%) vs 27 of 51 [52.9%]; aOR, 0.58)
Endoscopic response/remission: infliximab-treated participants were more likely to achieve 1-year endoscopic response (43 of 92 [46.7%] vs 6 of 30 [20.0%], aOR, 3.59) and endoscopic remission (31 of 92 [33.7%] vs 4 of 30 [13.3%]; aOR, 3.35)
In the discussion, the authors note only 1 head-to-head study in CD with ustekinumab. “The SEAVUE trial (NCT03464136) compared adalimumab and ustekinumab among biologic-naïve CD patients. Ustekinumab demonstrated similar efficacy for the achievement of clinical and endoscopic outcomes compared with adalimumab.23 Similar rates of CR at 1 year were reported in SEAVUE (64.9% ustekinumab vs 61% adalimumab) as in our analysis (57.3% ustekinumab vs 60% infliximab)…ustekinumabdemonstrated longer retention and lower immunogenicity and has practical advantages over adalimumab, including less frequent dosing intervals (every 8 weeks for ustekinumab vs every 2 weeks for adalimumab) while providing similar efficacy.”
My take: This study suggests that infliximab may be a little better than ustekimumab in biologic-naive patients due to the higher endoscopic response; however, the study was unpowered to provide a definitive answer. A prior study suggested similar endoscopic healing rates (P Riviere et al. Inflamm Bowel Dis 2023; 29: 923-931).
A previous study (SEAVUE) has suggested similar efficacy of ustekinumab and adalimumab in biologic-naive patients (post: SEAVUE: Head-to-Head Ustekimumab vs. Adalimumab) with ~60-65% clinical response at 52 weeks and ~30% endoscopic remission.
This current retrospective study sought to obtain ‘real-world’ data comparing anti-TNF agents (95 adalimumab, 61 infliximab) to ustekinumab (n=50). In the anti-TNF group, 44% (n=68) received concomitant immunomodulator therapy. Key findings:
At 3 months, clinical response rates were 86% in anti-TNF groups and 64% in the ustekinumab.
At 12 months, in adjusted multivariate analysis, clinical remission (based on Harvey-Bradshaw Index) was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab;P = .02).
“In our sensitivity analysis, a significant difference in terms of efficacy was only found between infliximab and ustekinumab.”
In those with ileocolonoscopy, endoscopic healing was similar (between 6-18 months): 58% of anti-TNF group and 61% of ustekinumab group.
2% of patients in the anti-TNF group had severe adverse events compared to none in the ustekinumab group; among patients receiving adalimumab, 1 patient had cerebral aspergillosis, 1 had a postinfectious macrophage activation syndrome, and 1 had severe folliculitis needing abscess drainage.
Drug persistence at 12 months was 87% in anti-TNF group and 88% in ustekinumab group.
The discussion notes that ‘real-world’ data is important as only ~30% of patients in a regular practice would fulfill the criteria to be included in clinical trials. However, in this retrospective (non-randomized) study, there were differences in the patient population that could affect response to treatment, including a higher rate of smokers in the anti-TNF group (29% compared to 12% in the ustekinumab group).
My take: While anti-TNF therapy, particularly infliximab, may be a little better based on clinical remission, the most objective marker of efficacy, endoscopic healing, was similar. Thus, it is not clear if anti-TNF therapy is more effective than ustekinumab. To achieve optimal results, many in the anti-TNF group received immunomodulator cotherapy and dose escalation.
Joel Andres, Chef & Philanthropist, World Central Kitchen
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.
Generally, in my view, “bad” inflammatory bowel disease (IBD) occurs when treatments are not working; though, many would argue that any IBD is bad IBD. Over the next few days, reviewed articles will focus on the problem of IBD that is not responding well to treatment.
In this retrospective study with 69 children with Crohn’s disease (CD) from 25 centers, the authors looked at the effectiveness of ustekinumab (UST) dose escalation which entailed reducing frequency to less than every 8 weeks. Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced.
Key findings:
Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively.
Fecal calprotectin level from 1100 (500–2300) to 515 (250–1469) µg/g (P = 0.012) 3 months post-escalation
Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively
In their discussion, the authors note that UST has not received FDA approval despite the fact that it has become a common second- and third-line biologic therapy for pediatric CD.
My take: This study supports the common practice of escalation of UST for children with active CD despite treatment at every 8 weeks.
Related Ustekinumab Studies:
J Meserve et al.Clin Gastroenterol Hepatol 2022; 20: 2728-2740. Open Access! Effectiveness of Reinduction and/or Dose Escalation of Ustekinumab in Crohn’s Disease: A Systematic Review and Meta-analysis In this article with 15 cohort studies in 925 adults with CD with inadequate response or loss of response to standard dose ustekinumab, on meta-analysis, 55% of patients achieved clinical response [with dose escalation]…61% of patients were able to achieve endoscopic response, including 29% who achieved endoscopic remission. Dose interval shortening alone recaptured response in 57% patients.
RS Dalal et al. Clin Gastroenterol Hepatol 2022; 20: 2399-2401. Predictors and Outcomes of Ustekinumab Dose Intensification in Ulcerative Colitis: A Multicenter Cohort Study This retrospective study looked at 108 adult patients with UC who had ustekinumab escalation; more than 40% required dose intensification. “Similar to our findings in Crohn’s disease, >50% of dose-intensified patients achieved corticosteroid-free remission….Patients with minimal/no response to induction had lower odds of remission after intensification.”
S Dansese et al.Clin Gastroenterol Hepatol 2022; 20: 2858-2867. Open Access! Early Symptomatic Improvement After Ustekinumab Therapy in Patients With Ulcerative Colitis: 16-Week Data From the UNIFI Trial This study, a post hoc analysis of UNIFI trial, found that an early (2 week) symptomatic remission with ustekinumab in 20.2% (P = .012) vs placebo (12.9%). The more extensive results reviewed in the article (Figure 2) showed increasing symptomatic remission rates at week 4 (32.9%), week 8 (44.7%), and week 16 (53,1%) with IV dose of 6 mg/kg. The biologic-naive group had higher symptomatic remission rates (69% at week 16).
Deepdene Park, Atlanta. Part of Olmstead Linear Park
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.
In the validation cohort of 81 MREs, the weighted global PICMI correlated well with the radiologist global assessment (r = 0.85; P < .001) and with the simple endoscopic score in a subsample with ileocolonic disease (r = 0.63; P < .001).
Interobserver and test-retest reliability were high (interclass correlation coefficients, 0.84 and 0.81, respectively; both P < .001)
Transmural healing was defined as PICMI ≤10 and response as a change of >20 points with excellent discriminative validity (area under the receiver operating characteristic curve = 0.96
My take: This study identifies a specific MRI index (PICMI) that is reliable for assessing the entire bowel in pediatric CD and does not require intravenous gadolinium or rectal enema. By using a standardized tool, similar to SEMA-CD for ileocolonoscopy, this will improve the usefulness of MREs.
Also noted: Link: Clinical support tool (sponsored by AGA) that provides individualized information on 2nd line therapy effectiveness (ustekinumab and vedolizumab) with regard to probability of achieving clinical remission, how quick to expect a response, and whether therapeutic drug monitoring is needed.
Compared with WD1 (typical Western Diet), PB2 (Plant-based diet 2) was associated with lower odds of active symptoms for CD (odds ratio [OR], 0.32
PB1 (Plant-based diet 1) was associated with lower odds of active symptoms for participants with UC (OR, 0.45; 95% CI, 0.23-0.90) but not for participants with CD (OR, 0.95
Diet PB1 (“Plant-based Diet 1”) was characterized by much higher intake of fruits, vegetables, plant-based proteins, and cooked grains than most other dietary clusters. There was low water intake in favor of juices and other beverages. There was otherwise average intake of added fats and oils, sugars, seafood, and dairy products, and modest intake of meats, eggs, mixed grains, and breads.
Diet PB2 (“Plant-based Diet 2”) was characterized by high intake of fruits, vegetables, plant proteins, and cooked grains and low intake of animal proteins (especially red and cured meats), added fats, sweetened beverages, sweet bakery products, other desserts, eggs, and breads. There was also a reduction of other beverages in favor of water. There was otherwise an average intake of seafood and dairy products.
Background: The current chart review study evaluated the longer-term effectiveness and safety of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells).; n=43 treated patient and n=46 controls.
Key findings:
At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively.
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:
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.
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.
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.
gutsandgrowth 