Vedolizumab -Not Likely to Help Primary Sclerosing Cholangitis

A recent retrospective study (TJ Laborda et al. JPGN 2020; 71: 459-464 Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium) indicates that vedolizumab (VDZ) is unlikely to be helpful for primary sclerosing cholangits (PSC).

VDZ was initiated at median age of 16 years [IQR 15–18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis.

Key findings:

  • Overall, there was a mild increase in median GGT after initiation of VDZ. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response (defined as GGT <50 or at least a 75% decline) after 9 to 12 months
  • For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response

In the discussion, the authors note that their findings are in agreement with three retrospective studies in adults which have shown that VDZ is not effective for PSC in patients with IBD.

My take: This study indicates that VDZ is not likely to help with PSC, though 62% of IBD patients had improvement in their GI disease.

From The Onion

IBD Briefs -October 2020

EV Loftus et al.  AP&T  2020; 52: 1343-1365. Full text: Long‐term safety of vedolizumab for inflammatory bowel disease

GEMINI long‐term safety (LTS) study results –initiated 2009:

  • Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks. Total of 7999 patient years of vedolizumab exposure.
  • Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients.
  • There were no new trends for infections, malignancies, infusion‐related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy
  • Conclusion from authors: “The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns.”

Related blog posts:

AS Faye et al. Inflamm Bowel Dis 2020; 26: 1368-1376. Fertility Impact of Initial Operation Type for Female Ulcerative Colitis Patients (link includes video abstract)

Surgical options include Ileal pouch–anal anastomosis (IPAA), rectal-sparing colectomy with end ileostomy (RCEI), and ileorectal anastomosis (IRA). Conclusions based on “a patient-level state transition microsimulation in TreeAge Pro:”… “Despite an increased risk of infertility, our model results suggest that IPAA may be the optimal surgical strategy for female UC patients aged 20–30 years who desire children. For patients aged 35 years, RCEI should additionally be considered, as QALYs for RCEI and IPAA were similar.”   In older age group, RCEI’s increase rate of childbirth (28%), decrease time to childbirth (14 months) and 77% reduction in IVF are important factors.

Related blog posts:

R Tariq et al. Inflamm Bowel Dis 2020; 26: 1415-1422. Efficacy of Fecal Microbiota Transplantation for Recurrent C. Difficile Infection in Inflammatory Bowel Disease

In this retrospective study with 145 patients,  the overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1–51) months. The authors concluded that “fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.”

Related blog posts:

Isle of Palms (July 2020)

 

“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

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

 

IBD Update -September 2020

EM Kim et al. Inflamm Bowel Dis 2020; 26: 1232-38. Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases n=65 patients. In IBD cohort, colonic eosinophilia (340 +/- 156 vs 236 +/- 124) was associated with clinical non-response to vedolizumab (as was prior anti-TNF treatment). In those with ulcerative colitis, mean eosinophil count was 438 in nonresponders compared to 299 in responders. In those with Crohn’s disease, colonic biopsies showed a non-significant increase in eosinophil count in non-responders compared to responders: 352 vs. 232.

MA Sofia et al. Inflamm Bowel Dis 2020; 26: 1251-9. Poor Sleep Quality in Crohn’s Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery

  • Ninety-two CD and 82 control subjects
  • Crohn’s disease subjects with Pittsburgh Sleep Quality Index (PSQI) >5 more often had inflammatory phenotypes and reported increased benzodiazepine and psychiatric medication use. Crohn’s disease subjects with PSQI >5 also reported more night awakenings due to pain and bathroom use.
  • The PSQI correlated with HBI
  • PSQI >8 was predictive of surgery or hospitalization (hazards ratio 5.37; 95% confidence interval, 1.39-27.54).

My take: This study indicates that poor sleep is a marker for increased adverse outcomes/disease activity.  It may be that sleep disturbance is due to increased disease activity or this may be a bidirectional issue in which poor sleep triggers more disease activity as well.

A Ricciuto et al. Clin Gastroenterol Hepatol 2020; 18: 1509-1517. Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment

This retrospective study provides additional information on the observation that children with PSC often have subclinical disease; it is similar to a prospective study by the same group in 2018 (n=37):  (prior blog post: Active Colitis More Likely in Children in Clinical Remission Who Have IBD and PSC) Key finding: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Conclusions: “Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.”

Comparative Efficacy: Vedolizumab vs Anti-TNF Agents

M Bohm et al. AP&T: 2020; July 2020 https://doi.org/10.1111/apt.15921 Full text: Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn’s disease

Thanks to Ben Gold for this reference.

Methods: Retrospective observational cohort (May 2014–December 2017) propensity score‐weighted comparison of vedolizumab vs TNF‐antagonist therapy (infliximab, adalimumab, certolizumab) in CD.  This study included 1266 patients (n = 659 vedolizumab).

Key findings:

  • Rates of non‐infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012‐0.242) were significantly lower with vedolizumab vs TNF‐antagonist therapy.
    • These events included severe arthralgias in 3 vedolizumab-treated patients.  For anti-TNF recipients, events included hypersensitivity or infusion reactions (n = 6), drug‐induced psoriasis (n = 6), drug‐induced lupus (n = 5), severe liver function test abnormalities (n = 3), skin rash (n = 2), lung cancer (n = 1) and jaw or hip necrosis (n = 2).
  • Rates of serious infections (OR 1.183, 95% CI 0.786‐1.795), were NOT significantly lower with vedolizumab vs TNF‐antagonist therapy.
    • “The risk of serious infections with biologic therapy is largely driven by disease activity and concomitant use of immunosuppressive agents…. the higher concomitant use of steroids among the vedolizumab‐treated patients in our cohort may therefore help to explain the lack of observed difference in risk for serious infections between agents.”
  • No significant difference was observed between vedolizumab and TNF‐antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707‐1.228), steroid‐free clinical remission (HR 1.250, 95% CI 0.677‐2.310) or endoscopic remission (HR 0.827, 95% CI 0.595‐1.151).
    • “Our observational cohort study was not designed to be a noninferiority study, and the safety and effectiveness comparisons were exploratory in nature.”
  • The efficacy of vedolizumab in this study is more impressive given that 91% of the patients had prior anti-TNF therapy.
    • “Exploratory subgroup analyses suggested that vedolizumab might be superior to subcutaneous TNF‐antagonist therapy for the achievement of clinical remission and steroid‐free clinical remission in TNF‐antagonist–naïve patients.”
  • TNF‐antagonist therapy was associated with higher treatment persistence compared with vedolizumab.

My take: This article shows that clinical experience with vedolizumab is quite good and compares favorably with anti-TNF agents.  Randomized head-to-head studies are needed, though, to truly determine efficacy in similar populations.

Related blog posts:

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.

Related blog posts:

IBD Update -July 2020

X Roblin et al. Gut 2020; DOI: 10.1136/gutjnl-2019-319758 Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Key Findings:

  • Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy
  • At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22% versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy

RC Ungaro et al. Clin Gastroenterol Hepatol 2020; 18: 1152-60.  The authors retrospectively analyzed 3178 patients with Crohn’s disease and found that stopping mesalamine therapy in individuals who were starting biologic therapy did NOT increase their risk of adverse clinical events.  They caution that their findings should be validated in a prospective study.

J Wang et al. AP&T. https://doi.org/10.1111/apt.15766. Full Text: Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease Key finding: “Complete resolution with topical corticosteroids and calcineurin inhibitors alone were low (14% and 13% respectively). Higher rates of complete resolution were reported with anti‐tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%).”

B Verstockt et al. Clin Gastroenterol Hepatol 2020; 18: 1142-51. The authors found that expression of 4 genes in colon tissue could be used to predict which patients will enter endoscopic remission with vedolizumab therapy.  Given the increasing number of expensive therapies for IBD, the ability to predict likely success with treatment rather than selecting empirically would be a huge advance.

ST Leach et al. JPGN 2020; 70: 580-5. The authors found that fecal calprotectin was overall the best fecal biomarker for pediatric Crohn’s disease (=156 patients); however, FA12  (aka S100A12) at 5 mcg/g predicted mucosal healing with greater specificity (87% vs 70%) –though this is related in part to the cut-off values. For calprotectin to have greater specificity (>90%), a cut-off of <100 mcg/g lowered the sensitivity to 63%. FA12 also performs better in younger children as calprotectin levels are higher in this age group in healthy children.

Pipeline Medications for Ulcerative Colitis (Part 1) & Face Mask Shortages

Before getting to today’s post, I wanted to provide a link on why we are desperately short of face masks in the midst of this crisis: NY Times: How the World’s Richest Country Ran Out of a 75-Cent Face Mask

An excerpt:

The answer to why we’re running out of protective gear involves a very American set of capitalist pathologies — the rise and inevitable lure of low-cost overseas manufacturing, and a strategic failure, at the national level and in the health care industry, to consider seriously the cascading vulnerabilities that flowed from the incentives to reduce costs…

Given the vast global need for masks — in the United States alone, fighting the coronavirus will consume 3.5 billion face masks, according to an estimate by the Department of Health and Human Services — corporate generosity will fall short. People in the mask business say it will take a few months, at a minimum, to significantly expand production…

Hospitals began to run out of masks for the same reason that supermarkets ran out of toilet paper — because their “just-in-time” supply chains, which call for holding as little inventory as possible to meet demand, are built to optimize efficiency, not resiliency.

My take: Conserve, conserve, conserve PPE -supply chains meeting the need is NOT imminent.

—————

Several articles from Gastroenterology highlight emerging medications for ulcerative colitis (UC).

Two of the studies:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 550-61.
  • WJ Sandborn et al. Gastroenterol 2020; 158: 562-72.

The first study was a phase 2 randomized trial of etrasimod which is an oral selective sphingosine 1-phosphate receptor modulator.  A total of 156 patients were randomized into 3 groups: placebo, 1 mg etrasimod, and 2 mg etrasimod.

Key findings (graphical abstract):

In the second phase 3, double-blind, double-dummy study, Sandborn et al show that, after the initial 2 intravenous doses,  among patients with an initial response subcutaneous vedolizumab (108 mg every 2 weeks) had similar effectiveness to intravenous vedolizumab (300 mg every 8 weeks); both SC and IV vedolizumab resulted in higher clinical remission rates compared to placebo at 52 weeks in the 216 patients: 46.2%, 42.6%, and 14.3% respectively.

Full text link: Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis

Real-World Vedolizumab: Better Than Expected

Two recent studies indicate that vedolizumab is performing better than expected in the “real world.”

  • JL Koliani-Pace et al. Inflamm Bowel Dis 2019; 25: 1854-61
  • DM Faleck et al. Clin Gastroenterol Hepatol 2019; 17: 2497-2505.

In the first study, the researchers used 2 data sets (VICTORY cohort, n=1087, & the Truven cohort, n=2574)  to compare vedolizumab in two separate eras; the early era was May 2014-June 2015  and the later era was July 2015-June 2017.

Key findings:

  • Patients with Crohn’s disease (CD) in the VICTORY cohort during the second era had better clinical remission rates: 40% vs 31% and better mucosal healing rates 58% vs 42%
  • Later era patients with ulcerative colitis (UC) in the Truven database had lower rates of IBD-related hospitalization (22.4% vs. 9.6%) and surgery (17.2% vs. 9.4%)
  • In the later era, patients were more likely to be biologic naive.

This study indicates that, overall, patients treated in the first era were likely more sick and less likely to respond to vedolizumab.  The authors’ note that this could be a ‘warehouse effect’ whereby “patients treated within the first year of a drug’s approval are likely representative of a select group of high-risk patients who are refractory to currently available therapies and are being warehoused on ineffective and undesirable therapies (ie. chronic steroid) to bridge them through until a promising agent is approved by the FDA.”

In the second study, the authors retrospectively examined 650 patients with CD and 437 with UC who were treated between 2014-16.  Patients who had a more recent diagnosis of CD (≤2 years) fared better than those with more long-standing disease.

Key findings:

  • Early-stage CD vs. later-stage CD clinical remission rates: 38% vs 23%
  • Early-stage CD vs. later-stage CD with corticosteroid-free remission: 43% vs 14%
  • Early-stage CD vs. later-stage CD with endoscopic remission: 29% vs. 13%
  • UC disease duration did not associate with response to vedolizumab

My take: Taken together, these studies indicate that vedolizumab in the real world may outperform the results of the landmark studies which helped garner FDA approval.  In patients who are less sick and have not been considered refractory to multiple treatments, response rates to vedolizumab are higher.

Related blog posts:

Highlights in IBD from Two 2019 Meetings: American College of Gastroenterology and United European Gastroenterology Week

Gastroenterology & Hepatology. December 2019 – Volume 15, Issue 12, Supplement 5

Excerpts from William Sandborn Commentary which are at the end of this supplement along with references:

Vedolizumab

In the VARSITY study (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis), 769 patients with ulcerative colitis were randomized to a year of therapy with either adalimumab at the US Food and Drug Administration (FDA)-approved dose or vedolizumab at the FDA-approved dose…This shows that the idea that vedolizumab (and anti-integrin therapy) is slower-acting than anti-TNF therapy is not correct, and that both of these classes of drugs can work fairly quickly in a number of patients.

Dr Brian Bressler and colleagues looked at the effectiveness of anti-TNF therapy in the real world when used second line after failing first-line biologic therapy with vedolizumab…The study conducted by Dr Bressler and colleagues, which included both Crohn’s disease patients and ulcerative colitis patients, found that the results were fairly similar whether patients received first-line biologic therapy with an anti-TNF agent or whether patients received first-line therapy with vedolizumab… It is generally thought that vedolizumab is a safer therapy than anti-TNF therapy, so with the finding from this study, a reasonable treatment approach could be to start with vedolizumab and see if it works

Dr Christina Chambers and colleagues identified outcomes for pregnancy in 223 women, 53 of whom received vedolizumab. The researchers found that there were no major structural birth defects reported in the vedolizumab group, compared to 5.7% and 5.3% in the disease-matched group and healthy control group, respectively. Thus, there seemed to be no signal for an increased malformation risk in patients who were undergoing treatment with vedolizumab and became pregnant.

Adalimumab

The SERENE trials are a set of head-to-head trials, one for ulcerative colitis and one for Crohn’s disease, comparing standard-dose adalimumab to a more intensive induction regimen of adalimumab…

For both ulcerative colitis and Crohn’s disease, the SERENE trials showed that the current FDA-approved dosing regimen is effective and that more intensive induction therapy does not improve outcomes over time. Thus, there is no utility in giving high induction doses. 

Tofacitinib

Over 1000 patients who had been treated with tofacitinib were examined…during induction and maintenance of the placebo-controlled portion of the tofacitinib clinical trials, there were a total of 5 deep vein thrombosis and pulmonary emboli events. All 5 occurred in patients who were receiving placebo; none of these events occurred in patients who were receiving tofacitinib…[And] There was a total of 5 deep vein thrombosis and pulmonary emboli events during this long-term extension…Looking at the ulcerative colitis clinical trial data that I presented, it is somewhat reassuring that we did not see the same elevation in risk for deep vein thrombosis and pulmonary emboli that was seen in the high-risk rheumatoid arthritis patient population.

Mont Royal (Montreal)