Efficacy and Safety of Odevixibat with Alagille Syndrome (ASSERT Trial)

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N Ovchinsky et al. The Lancet Gastroenterology & Hepatology, Volume 9, Issue 7, 632 – 645. Open Access! Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Methods: “The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries” with 52 patients (enrolled 2021-2022). “The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24.” The treatment group received odevixibat 120 µg/kg per day.

Key findings:

  • There were improvements in both scratch scores and bile acid concentrations
  • There were improvements in sleep parameters including falling asleep and ability to sleep without a caregiver
  • Adverse events: diarrhea was reported in ten (29%) of 35 patients who received odevixibat and in one (6%) of 17 patients who received placebo; all cases were mild in severity and no cases of diarrhea led to treatment interruption or discontinuation

Scratch Scores:

Bile Acid Levels

Other points:

  • Overall, 50 (96%) of the 52 patients chose to enter the open-label extension study
  • The authors note that this is the first randomized placebo-controlled trial for Alagille syndrome
  • A direct comparison of odevixibat and maralixibat in patients with Alagille syndrome is complicated by differences in study design and endpoints across the their studies

My take (borrowed in part from authors): “As pruritus is a major driver of liver
transplantation in patients with Alagille syndrome, these results suggest that odevixibat could have the potential to delay or prevent liver transplantation”

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Hollywood Beach, FL

Safety of JAK Inhibitors Compared to Anti-TNF Agents

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C Crist. GI & Hepatology News; 11/20/24: In IBD Patients, No Increased Risk for MACE Seen for JAK Inhibitors vs Anti-TNF

Background: There have been concerns that JAK inhibitors (JAKi), like tofacitinib (Xeljanz) and upadacitinib (Rinvoq) could increase the risk of major adverse cardiovascular events (MACE); as such, the FDA has placed warnings on these medications (see blog post: FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks).

An excerpt:

According to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting, .

Alsakarneh and colleagues conducted a retrospective cohort study using the TriNetX database to identify adult patients with IBD who were treated with JAKi or anti-TNF therapy after diagnosis. After matching patients in the JAKi cohort [n=3740] with patients in the anti-TNF cohort [n=3740], the research team looked for MACE and VTE within a year of medication initiation…

After excluding those with a history of a prior cardiovascular event, 57 patients (1.76%) in the JAKi cohort developed MACE, compared with 63 patients (1.94%) in the anti-TNF cohort. There weren’t significant differences between the groups in MACE (adjusted hazard ratio [aHR], 0.99) or VTE (aHR, 0.9).

Among patients aged ≥ 65, 25 patients (5.3%) in the JAKi cohort developed MACE, as compared with 30 patients (6.4%) in the anti-TNF cohort.

My take: Several studies now have not identified an increased risk of JAKi compared to other therapies for IBD. Perhaps, this will lead to a change in labeling by the FDA which has stated that JAKi should be used only in those with prior anti-TNF failure.

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Museum of Illusions (Atlantic Station)
This “bulging squares” illusion has straight lines across and vertically when you are right in front of it.

Efficacy of Mirikizumab in Moderate-to-Severe Crohn’s Disease (VIVID-1 Study)

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M Ferrante et al. The Lancet 2024; https://doi.org/10.1016/S0140-6736(24)01762-8. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study

Methods: VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study which enrolled 1150 patients with moderate-to-severe Crohn’s disease. There were three treatment groups: mirikizumab group, ustekinumab group, and placebo group. In each group, 48-49%were considered “biologic-failures” including 45-46% who were anti-TNF failures.

Key findings:

Discussion points:

Early treatment effect: “Symptomatic improvement was evident as early as week 4 accompanied by a statistically significant reduction in high-sensitivity CRP and faecal calprotectin, and endoscopic response was seen at week 12.”

Compared to ustekinumab: “Mirikizumab reached non-inferiority versus ustekinumab for clinical remission by CDAI at week 52…mirikizumab showed statistically significantly greater improvements from baseline in fecal calprotectin and CRP compared to ustekinumab.
In addition, a greater percentage of patients reached the combination endpoint of endoscopic response and clinical remission by CDAI at week 52.”

Comparison across treatment trials: “. At week 52, 45∙4% of patients treated with mirikizumab met the endpoint of clinical remission by CDAI in the treat-through analysis with composite endpoint, 54∙1% met the endpoint in the treat-through analysis, and 64∙3% met the endpoint in the responder analysis. This example, with a range of nearly 20% percentage points depending on analysis type, shows the profound limitations in comparing
unadjusted outcomes across phase 3 trials.” The authors note other differences in trial design between VIVID-1 and SEQUENCE (risankizimab) and state “no conclusions on
relative efficacy can be drawn.”

My take: This study shows that mirikizumab is effective in adults with moderate-to-severe Crohn’s disease with and without prior biologic treatments. Pediatric studies are underway.

Infliximab Thresholds with Subcutaneous vs Intravenous Administration for Crohn’s Disease

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SN Hong et al. AP&T 2024; 0:1–10. doi.org/10.1111/apt.18354. Subcutaneous Infliximab Concentration Thresholds for Mucosal and Transmural Healing in Patients With Crohn’s Disease

Background: The exposure–response relationship for the intravenous (IV) formulation of infliximab is well established, with multiple studies demonstrating that higher trough concentrations (C-trough) are associated with improved patient outcomes…However, the 2-week cycle of subcutaneous administration showed many-fold higher C-trough than the 8-week cycle of IV-IFX. Direct comparison of C-trough between SC- and IV-IFX is not appropriate because of different bioavailability and concentration–time profile. It is also not appropriate to apply the C-trough thresholds that predict achieving the therapeutic targets for IV.

This was a cross-sectional retrospective study with 124 patients with Crohn’s disease (CD) who had received SC-IFX maintenance therapy for ≥6 months. SC-IFX C-trough was measured immediately before SC-IFX injection. Key findings:

  • Mucosal healing (MH) was noted in 77.9% (74/95) and transmural healing (TH) in 36.3% (37/102).
  • SC-IFX C-trough was significantly higher in patients with MH (24.1 vs.16.9 μg/mL; p=0.001) and TH (26.0 vs. 20.5 μg/mL; p=0.007) than in those without.

Discussion:

Target trough levels: In this study, the authors found that “the C-trough thresholds for clinical remission, biochemical remission, MH and TH were 12, 16, 18 and 30 μg/mL, respectively, based on ROC analysis. The C-trough of SC-IFX increased with the depth of remission.”

Why trough level targets may differ between IV administration and SC: Administration via the IV route results in early and rapid peak concentration followed by a steady decline to trough, whereas administration via the SC route has slower absorption, lower bioavailability, lower peak concentration and smaller differences between peak and trough concentrations.

The authors note that a study by Ye et al (United European Gastroenterology Journal; 2020: 8: 385–386) with 55 patients found that a C-trough >26.6 mcg/mL achieved clinical remission and fecal calprotectin levels <250 mcg/g at week 54 in 79% and 91% respectively compared to 46% and 62% in those with with C-trough <16.4 mcg/g.

These C-trough levels are significantly higher that the median C-trough levels of standard dosing (120 mg biweekly) in a phase 1 dosing RCT which was only 13.3 mcg/mL (S Schreiber et al. Gastroenterology 2018; 154: 1371). The dosing of 180 mg and 240 mg biweekly resulted in C-trough levels of 19.9 mcg/mL and 26.5 mcg/mL respectively.

My take: This study suggests that therapeutic drug monitoring will have different targets with SC-IFX than with IV-SC. SC formulations will offer more convenience. However, more effort will be needed to make sure patients are adherent with therapy in order to achieve optimal outcomes.

Related study: S. N. Hong, J. Hye Song, S. Jin Kim, et al. Inflammatory Bowel Diseases 30 (2024): 517–528. One-Year Clinical Outcomes of Subcutaneous Infliximab Maintenance Therapy Compared With Intravenous Infliximab Maintenance Therapy in Patients With Inflammatory Bowel Disease: A Prospective Cohort Study. In this prospective study with 61 patients, SC IFX switch induced a higher 1-year durable remission rate than continuing IV IFX in patients with IBD during scheduled maintenance therapy.

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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.

Case Study: Pediatric Emergency from Magnet Ingestion

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G Prasad, V Jain. N Engl J Med 2024;391: e48. Small-Bowel Obstruction and Intestinal Fistula from Accidental Ingestion of Magnets

Case presentation excerpt:

A previously healthy 18-month-old girl was brought to the emergency department with sudden-onset abdominal distention that had been preceded by 3 days of diarrhea and 1 day of vomiting…an emergency exploratory laparotomy was performed. An ileocecal fistula (Panel B, circle) created by the union of three magnetic beads was identified (arrow, cecum; asterisk, ileum), and dilated loops of bowel were noted. The bowel was repaired. The patient was discharged after five days.

My take: There are a lot kids admitted for multiple magnet ingestion. Even in well-appearing children, due to concerns for complications, they are often observed until progression of the magnets. However, it does seem that many do not advance well after working their way to the cecum.

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Vonoprazan Treatment of Heartburn in Randomized Study of Patients with Non-Erosive Reflux Disease

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L Laine et al. Clin Gastroenterol Hepatol 2024; 22: 2211-2220. Open Access! Vonoprazan is Efficacious for Treatment of Heartburn in Non-erosive Reflux Disease: A Randomized Trial

This was a randomized trial (n=772) in patients diagnosed with non-erosive reflux disease (NERD) comparing vonoprazan (10 mg and 20 mg) versus placebo for heartburn relief. Reflux was NOT confirmed with ambulatory pH monitoring.

Key findings:

  • The percentage of 24-hour heartburn-free days was 27.7% for placebo vs 44.8% for vonoprazan 10 mg (P < .0001) and 44.4% for vonoprazan 20 mg ( P < .0001).
  • The results were similar between both doses of vonoprazan
  • The benefit of vonoprazan appeared to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. 
  • In a post-hoc analysis, there was a very small response in patients without prior PPI response compared to placebo: There was a possible trend to fewer (7%–9%) 24-hour heartburn-free days with vonoprazan in those without prior PPI response

Discussion points: “Post hoc analysis raised the possibility that patients who previously had not responded to PPIs may have a somewhat lower response to vonoprazan. This is not unexpected, given that patients not responding to PPIs are less likely to have heartburn due to acid reflux” and more likely to have functional heartburn. The treatment effect of vonoprazan was less clear in the subgroup of patients with NERD and with severe heartburn “It is conceivable this group included a higher proportion of subjects with functional heartburn, a condition that is generally not responsive to acid inhibition.”

My take: Vonoprazan is more effective than placebo for heartburn in patients with NERD. However, the absence of definite improvement in the patients with lack of prior PPI response along with the lack of difference between the 10 mg and 20 mg vonoprazan groups indicates that this therapy should NOT be used routinely in patients with NERD in the absence of documented reflux based on ambulatory pH studies.

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Effects of Thiopurine Withdrawal in Randomized Trial of Vedolizumab-Treated Patients with Ulcerative Colitis

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A Pudipeddi et al. Clin Gastroenterol Hepatol 2024; 22: 2299-2308. Open Access! Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Methods: This was a multicenter randomized controlled trial recruited UC patients (n=62) on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine.

Key findings:

  •  At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL versus 15.9 μg/mL, respectively, P = 0.36).
  • The continue group had significantly higher fecal calprotectin remission (calprotectin <150) (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Clinical and endoscopic remission favored the continue group though this did not reach statistical significance.
  • Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6–146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3–33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.

Discussion: “In Australia, requirements are for UC patients to have failed at least 3 months of an immunomodulator before vedolizumab initiation. Consequently, UC patients are typically on combination therapy initially, and hence this study was designed as a withdrawal trial.” The authors note that previous studies have not shown superior outcomes with combination therapy (See blog post: No Benefit of Combination Therapy with Ustekinumab or Vedolizumab). “However, methodological flaws, heterogenous outcomes, and shorter durations of treatment limit these findings.”

My take (borrowed from authors): “Thiopurines might provide an incremental benefit to patients with UC using vedolizumab, … independent of vedolizumab pharmacokinetics.”

Related study: C Yzet et al. Clin Gastroenerol Hepatol 2021; 19: 668-679. Full Text: No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis

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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.

Understanding Trichuriasis (Whipworm) in Young Children: A Case Study

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G Ding et al. N Engl J Med 2024;391: e34. DOI: 10.1056/NEJMicm2406623. Trichuriasis

Case report: A 2-year-old boy from a rural village in China was brought to the pediatric clinic with a 6-month history of diarrhea and poor weight gain. Laboratory studies showed iron-deficiency anemia, eosinophilia, and occult blood in the stool.

The worms, which were 3 to 4 cm in length, were identified as Trichuris trichiura — also known as human whipworm infection…Trichuriasis results from the ingestion of soil contaminated by whipworm eggs. Adult worms mature in the large intestine and affix themselves there by threading into the mucosa. Trichuriasis is usually asymptomatic but may result in diarrhea and growth retardation in cases of heavy infection, especially in young children. The child’s diarrhea resolved after treatment with albendazole.

CDC Link: Trichuriasis “The adult worms (approximately 4 cm in length) live in the cecum and ascending colon… The females begin to oviposit 60 to 70 days after infection. Female worms in the cecum shed between 3,000 and 20,000 eggs per day. The life span of the adults is about 1 year.”

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Pancreatic Cancer Surge in Young Adults –Why It has NOT Caused an Increase in Deaths

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11/18/24 NY Times, G Kolata: Pancreatic Cancer Surge May Be Less Worrisome Than It Seemed (behind paywall)

An excerpt:

One of the first warnings came in a paper published in 2021. There was an unexpected rise in pancreatic cancer among young people in the United States from 2000 to 2018… a new study published on Monday in The Annals of Internal Medicine suggests, the whole alarm could be misguided.

The authors of the paper, led by Dr. Vishal R. Patel, a surgical resident at Brigham and Women’s Hospital in Boston, did not dispute the data showing a rising incidence. They report that from 2001 to 2019 the number of young people — ages 15 to 39 — diagnosed with pancreatic cancer soared. The rate of pancreatic surgeries more than doubled in women and men…

With more pancreatic cancers in young people, there should be more pancreatic cancer deaths. And there were not. Nor were more young people getting diagnosed with later-stage cancers. Instead, the increase was confined to cancers that were in very early stages.

Many cancers will never cause harm if left alone, but with increasingly sensitive tools, doctors are finding more and more of them. Because there usually is no way to know if they are dangerous, doctors tend to treat them aggressively…It’s the hallmark of what researchers call overdiagnosis: a rise in incidence without a linked rise in deaths..

The sudden rise in pancreatic cancer incidence is largely being driven by another type of tumor — endocrine cancers [rather than the more dangerous adenocarcinomas]. They tend to be indolent, taking years or even decades to grow and spread, but occasionally they can turn malignant…

“A lot of patients say, ‘Get it out,’” said Dr. Adewole S. Adamson, an author of the new paper and an overdiagnosis expert at the University of Texas at Austin. “When someone tells you that you have cancer you feel like you have to do something.”

But, said Dr. William Jarnagin, a pancreatic cancer specialist at Memorial Sloan Kettering Cancer Center, removing early stage endocrine tumors “has never been proven to be a good strategy.”

My take: More cases of pancreatic tumors are being detected with the increased use of cross-sectional imaging (eg. CT scan, MRI). It is helpful to know that the increase in (mainly) pancreatic endocrine tumors is not leading to more deaths. Yet, each individual case presents some difficult decisions.

Related blog post:

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.

From the Museum of Illusions (Atlantic Station, Atlanta):

AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis –The Good and The Bad

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S Singh et al. Gastroenterol 2024; 167: 1307-1343. Open Access! AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis

This is a recent clinical guideline intended to serve as the starting point of a “living guideline” for adults with moderate-to severe ulcerative colitis.

  • The good news is that the AGA plans to update these guidelines semi-annually. The bad news is that this guideline does not provide the best advice.
  • It lumps recommended treatments into broad categories rather than indicating which therapies have the most effectiveness.
  • It is useful that the guidelines specifically recommend against step up therapy.
FDA labelling recommends upadacitinib only in patients who have not responded to anti-TNF therapy

For a recent study that provided more direction into which medications are most effective for both UC and Crohn’s disease: PS Dulai et al. Gastroenterol 2024; 166: 396-408. Open Access! Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases (Summarized in blog post: Comparative Evidence and Positioning Advance Therapies for 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.