Role of Biosimilars in Inflammatory Bowel Disease

A cautionary note on biosimilars has been discussed in a recent review (DT Rubin et al. Gastroenterol & Hepatol 2016; 12: 741-51)

In the recently completed NOR-SWITCH study presented at the United European Gastroenterology Week 2016 meeting, “a total of 481 patients were recruited across 40 centers: all patients had been on stable treatment with the originator infliximab for at least 6 months…When looking specifically at IBD patients, disease worsening was noted in 21.2% of originator infliximab-treated patients and 36.5% of CT-P13-treated Crohn’s disease patients (n=155).”  The 15% difference did not reach statistical significance, but is concerning.  The authors state that “subtle postranslational modifications unique to the biosimilars may be sufficient to lead to antidrug antibody formation with associated loss of response.  Also, it is noted that this study did not include endoscopic evaluation.

The authors note that therapeutic monitoring worked with biosimilar product using available infliximab assays.

My take: We still have a lot to learn.  The preliminary message, until more studies are available, indicate that switching stable patients could increase risk of losing response.

Related blog posts:

Puerto Rico

Puerto Rico

Here’s What I Really Want to Know about an MRE Study –What is the Correlation with PGA?

A nice pediatric study (CG Sauer et al. JPGN 2016; 62: 378-83) provides data on 101 children from a single center who underwent MRE to evaluate their Crohn’s disease.  This study was a retrospective chart review using a prospectively maintained MRE database.  All of the children in this study underwent MRE greater than 180 days after diagnosis.  MRE was ordered at the discretion of the treating gastroenterologist. Median followup was 2.8 years after MRE.

Key findings:

  • MRE correlated with meaningful clinical outcomes. Of the 65 with active inflammation on MRE, only 44.6% achieved clinical remission (another 30% progressed to mild disease activity). Of the 36 without active inflammation, 88.9% achieved clinical remission.
  • Children with active inflammation on MRE were more likely to undergo surgery (18.5% vs. 2.8%) and more likely to have medication changes (44.6% vs. 8.3%).

While this population may have had more disease than those who did not undergo MRE (since it was done at the discretion of gastroenterologist), what would interest me would be the correlation with the physician global assessment.  A rough calculation would suggest that only 40% of these patients achieved a clinical remission which is well below ImproveCareNow reported benchmarks, but not much different from previous studies using objective markers.  Furthermore, it would be of interest to look at whether individual clinicians incorporated their abnormal MREs into their assessment of PGA.  If the patient was doing well clinically but their MRE was markedly abnormal or even mildly abnormal, were these patients classified as in remission or otherwise.

My take: MRE is an excellent & expensive tool to assess for mucosal healing.  As our treatments continue to improve, MRE will be useful to monitor our progress.  How we incorporate our objective markers with our clinical markers needs further work.

Related blog posts:

 

Cancers Complicating Inflammatory Bowel Disease

In several prior posts, the issue of cancer and inflammatory bowel disease (IBD) has been discussed.  In my view, even the word “cancer” is so scary that it can make people make bad choices (related: Facts, “Misfearing” and Women’s Health | gutsandgrowth).  An up-to-date succinct summary (Laurent Beaugerie, M.D., Ph.D., and Steven H. Itzkowitz, M.D. N Engl J Med 2015; 372:1441-1452) provides a fairly good overview of “Cancers Complicating Inflammatory Bowel Disease.”

Key points:

  • “Smokers are overrepresented among the patients with Crohn’s disease…results in an excess rate of smoking related cancers.” (Smoking also is associated with more aggressive Crohn’s)
  • Colorectal cancers risk factors (Table 1), specific to IBD, include coexisting primary sclerosing cholangitis (PSC), and increasing duration & extent of colonic IBD.
  • A “progressive decrease in the excess risk of colorectal cancer in patients with IBD has been noted over time.”  This may be due to better control of inflammation, surveillance, and colectomy.  Still, the risk of colorectal cancer in patients with IBD is 1.5 to 2 times greater than the general population risk.
  • Small-bowel adenocarcinoma –risk is 20-30 times that of the general population, typically arises more than 8 years after diagnosis.  Absolute risk in those with disease more than 8 years is estimated at “0.5 per 1000 patient-years.”
  • Intestinal lymphomas –absolute risk is about 0.1 per 1000 patient-years.
  • Cholangiocarcinoma (CCA)–absolute risk is approximately “0.08 per 1000 patient-years.” CCA is mainly evident in patients with PSC who have a risk ~160 times the general population and lifelong risk of 5-10%.
  • Non-Hodgkin’s lymphoma –“whether TNF-alpha antagonists promote lymphomas by themselves in patients with IBD is difficult to assess…” A recent study found no excess risk in patients receiving TNF-alpha antagonists after adjustments for cotreatments.
  • Skin Cancers –nonmelanoma skin cancer, though not life-threatening, occur more often in those with current thiopurine usage.
  • HPV-Related Cervical Cancer –“it is still unclear whether the risk of HPV-related cervical cancer is intrinsically increased in woman with IBD or independently worsened by exposure to an immunosuppressant.”
  • Thiopurines: “after adjustment for confounders, current use of thiopurines for IBD has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7.”
  • TNF-alpha antagonists: “There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for IBD.”  However, more long-term data are needed.

Recommendations:

  • Figure 2 provides recommendations for colorectal cancer surveillance based on the American Gastroenterological Association (AGA), British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) recommendations. Typically, 8-10 years after diagnosis of colitis, starting surveillance (with chromoendoscopy if available) is recommended.  In patients with Crohn’s disease, “the excess risk appears when more than 30 to 50% of the colonic surface is ever involved.” However, with PSC, the excess risk of colorectal cancer is significant at the time of diagnosis.
  • For cholangiocarcinoma screening in those with PSC, “most experts recommend noninvasive annual imaging of the biliary tract (MRCP or ultrasound) and serum CA 19-9.”
  • For HPV, vaccination is recommended and regular Papanicolaou tests

Take-home message: Some cancers are increased in association with IBD.  However, the medications, particularly immunosuppressants, may reduce the incidence of inflammation-related cancers…or promote immunosuppression-related cancers.

Related blog posts:

Sandy Springs

Sandy Springs

Prospective Monitoring of Calprotectin for Crohn’s Disease

A recent study (full text link: Wright EK, et al. Gastroenterol May 2015 Volume 148, Issue 5, Pages 938–947) shows that stool calprotectin levels can be useful to monitor Crohn’s disease (Links from AGA twitter feed).  This study measured levels as part of The Post-Operative Crohn’s Endoscopic Recurrence (POCER) study.

Here’s the abstract, followed by some comments:

Background & Aims

Crohn’s disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa.

Methods

We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn’s disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn’s disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients.

Results

Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 μg/g before surgery to 166 μg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 μg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 μg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 μg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 μg/g at 6 months to 180 μg/g at 12 months and 109 μg/g at 18 months.

Conclusions

In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.

Some key points from the discussion:

  • The POCER study recently showed that postoperative endoscopic monitoring, together with treatment intensification for early recurrence, is superior to standard drug therapy alone in preventing disease recurrence, at least in the short term. However, such endoscopic monitoring is invasive, expensive, cannot be repeated frequently, and, in some patients, will yield a normal result.” [De Cruz, P., Kamm, M.A., Hamilton, A.L. et al. Crohn’s disease management after intestinal resection: a randomised trial. Lancet2014; (Epub ahead of print)]
  • The POCER study had all postoperative patients receive 3 months of metronidazole.  High-risk patients also received thiopurine or adalimumab (if thiopurine intolerant) therapy.  High-risk was defined as patients who were smokers, patients with perforating disease, or patients with 1 or more previous resections.
  • “In our study we have shown that FC concentration is increased markedly before surgery and decreases substantially after resection of all macroscopic disease at 6 months”
  • The present study has shown that FC concentration is sufficiently sensitive to monitor for recurrence of Crohn’s disease, and has a high enough negative predictive value to be confident that few patients with recurrence will be missed.” The authors, though, recommend serial measurement rather than relying on a single assay.
  • Calprotectin: “At each time point in our study, a cut-off value of 100 μg/g had an NPV of 90% or greater, with the best combination of sensitivity and specificity.”
  • An important limitation of these findings is that patients had to have all macroscopic disease removed at the time of surgery.  Thus, these findings are not generalizable to patients with residual upper gastrointestinal disease.
  • “These results confirm the accuracy, utility and superiority of fecal calprotectin compared with CRP or CDAI as a monitoring tool and screening test for endoscopic recurrence of Crohn’s disease in the postoperative population.”

Additional summary of this information on AGA Journals blog:  Measurement of Fecal Calprotectin.  An excerpt:

In an editorial that accompanies the article, Alain M. Schoepfer and James D. Lewis explain that the role of fecal calprotectin in assessing post-operative recurrence has been debated because of inconsistent results in mainly small studies. The strengths of the study of Wright et al include its large size, prospective design, endoscopic validation, and longitudinal inter-individual measurements of fecal calprotectin.

Tests for biomarkers such as fecal calprotectin can be repeated more frequently than colonoscopies. This advantage could overcome the lower levels of sensitivity with which single measurements of biomarkers detect recurrence. Schoepfer and Lewis say that studies are needed to determine the optimal frequency for measuring fecal calprotectin.

However, they conclude that measurement of fecal calprotectin could have an important role in monitoring Crohn’s disease recurrence after intestinal resection; it is clearly superior to measurement of c-reactive protein or CDAI score.

Proposed algorithm for using calprotectin: In the editorial, they propose that patients with low or medium risk of “permanent bowel dysfunction as a consequence of post-operative recurrence” could use fecal calprotectin measurements every 3-6 months.  They propose a cut-off of 50 mcg/g in those with medium risk and a cut-off of 100 mcg/g in those with low risk.  Those who exceeded cut-off would need colonoscopy.  Among high risk patients, they recommend proceeding directly to colonoscopy every 6-12 months to assess for recurrence.  All patients who had recurrence of disease greater than i1 would need treatment for recurrence. (Related gutsandgrowth blog: Only One Chance to Make a First Impression).

This year’s 22Q at the zoo was on May 17th, 2015:

22Q at the Zoo.  More than 100 zoos across the world participate to improve awareness of 22Q deletion syndrome

22Q at the Zoo. More than 100 zoos across the world participate to improve awareness of 22Q deletion syndrome.  With Karlene Coleman, Nancy Morris, and Jennifer Hochman.

New Mutations: Achalasia, Pseudoobstruction, & IBD

The ability to use whole exome sequencing and widely available genetic testing is yielding a plethora of new information regarding the genetic causes for many conditions.  In gastroenterology, here are a few recent examples:

  • Shteyer E, et al. “Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia.” Gastroenterology. 2015 Mar;148(3):533-536.e4. doi: 10.1053/j.gastro.2014.11.044. Epub 2014 Dec 3.
  • Bonora E, et al. “Mutations in RAD21 Disrupt Regulation of APOB in Patients with Chronic Intestinal Pseudo-Obstruction” Gastroenterology 2015; 148: 771-82.  Genetic defect in RAD21 identified in Turkish family with consanguinity; in addition, APOB48 serum levels was identified as a potential biomarker for intestinal pseudo-obstruction and intestinal ganglion numbers.
  • Alonso A, et al. “Identification of Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study.” Gastroenterology 2015; 148: 794-805. Variants in MAG11, CLCA2, 2q24.1, LY75 identified as associated with Crohn’s phenotypes.

For me, I am not sure whether these findings should be considered mundane or amazing. On the one hand, each of the findings helps understand these diseases; yet, I came across all of these articles in the span of 24 hours and from the same journal.

Mongerson -Phase II Data Available in NEJM

Previously, this blog noted that a phase II study showed that Mongerson, an oral SMAD7 antisense oligonucleotide, had promising data for moderate-to-severe Crohn’s: An Oral Oligonucleotide in the Crohn’s Treatment Pipeline …

The study has now been been published: NEJM 2015; 372: 1104-13.  Among patients who received 40 mg and 160 mg of mongerson, remission (CDAI <150) at 15 days was achieved in 55% and 65% respectively compared to 12% for 10 mg dose and 10% for placebo group.

The associated editorial (pg 1166-67) notes that only 18% of the patients with elevated C-reactive protein and randomized to the 40 mg and 160 mg doses normalized these levels at the end of the treatment period.  Thus, further trials will need to look more closely at objective biomarkers.

Unrelated but interesting -from John Pohl & Bryan Vartabedian’s twitter feeds:  “Food Babe” Exposed as a Fraud

Infliximab -Low Response in Young Kids (7 years and younger) with IBD

 JPGN 2014; 59: 758-62. The full abstract for this reference follows but the message from this retrospective study of 33 children is clear –a much smaller percentage of the youngest children respond to infliximab compared to older children, adolescents and adults. In the discussion, the authors note that younger children may need higher dosing to maintain good infliximab levels or the disease pathogenesis may be much different (eg. underlying immunodeficiency and different gene mutations).

Here’s the abstract (from JPGN twitter feed):

Background: Infliximab (IFX) is efficacious for induction and maintenance of remission in pediatric patients with moderate-to-severe inflammatory bowel disease (IBD). It has, however, not been studied in patients 7 years old and younger. Our aim was to characterize efficacy and safety of IFX therapy in this cohort.

Methods: This was a retrospective study of patients with IBD ages 7 years and younger, treated with IFX between 1999 and 2011. Medical records were reviewed for age of diagnosis, disease phenotype, therapy, surgery, IFX infusion dates, dose, and intervals. Outcome measures included physician global assessment, corticosteroid requirement, and adverse events.

Results: Thirty-three children (ages 2.4–7 years) were included. Twenty patients had Crohn disease, 4 had ulcerative colitis, and 9 had indeterminate colitis. Maintenance of IFX therapy at 1, 2, and 3 years was 36%, 18%, and 12%, respectively. Patients of age 5 years and younger had the lowest rates of maintenance of therapy at 25% at year 1, and 10% at years 2 and 3 combined. Nine percent of all of the patients demonstrated response measured by the physician global assessment and were steroid free at 1 year. There were 8 infusion reactions. There were no malignancies, serious infections, or deaths.

Conclusions: IFX demonstrated a modest response rate and a low steroid-sparing effect in patients with IBD 7 years old and younger. Although this is a limited study, there appears to be a trend for decreased sustained efficacy with IFX in this age group, particularly in children 5 years old and younger, when compared with the previously published literature in older children.