FDA Approves Adalimumab Biosimilar -But Will Enter U.S. Market in 2023!

October 31, 2018: FDA Approves Sandoz’s Biosimilar Adalimumab, Hyrimoz

An excerpt:

The FDA has approved Sandoz’s biosimilar adalimumab, Hyrimoz (adalimumab-adaz). 

The drug has been approved to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn disease, ulcerative colitis, and plaque psoriasis…

Despite today’s approval, US patients will have to continue to wait for access to Hyrimoz, as the biosimilar will not enter the US market until 2023. Earlier this month, Sandoz announced a global settlement of patent disputes with AbbVie over the drug. While the settlement allowed Sandoz to launch Hyrimoz in the European Union on October 16, 2018, it forestalled US market entry until September 30, 2023. 

My take: Why will this biosimilar be allowed in Europe but not U.$?

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Probiotics and Recurrent Abdominal Pain

Numerous articles have questioned the effectiveness of probiotics for many of the conditions for which they have been promoted.  A recent systematic review (T Newlover-Delgado, et al. JAMA PediatrPublished online December 28, 2018. doi:10.1001/jamapediatrics.2018.4575) concludes that probiotics “may be effective in the shorter term in improving pain in children with” recurrent abdominal pain (RAP). Thanks to Ben Gold for this reference.

This study extended findings from a 2009 Cochrane review (Huertas-Ceballos AA, et al Cochrane Database Syst Rev 2009; (1):CD003019).  In total, the authors identified 19 eligible studies; of these 15 were not included in the previous review. The most common probiotic studied was Lactobacillus rhamnosus GG in 5 trials.

Key findings:

  • At 0 to 3 months postintervention, ‘based on moderate-quality evidence (odds ratio [OR], 1.63, 95% CI 1.07-2.47; 7 studies, 772 children). The number needed to treat for an additional beneficial outcome was 8.” 
  • There were only 2 studies with results extending 3 to 6 months.  These studies also found reduction in pain in the probiotic-treated children, OR 1.94 (CI 1.10-3.43). 
  • Interestingly, the authors note that fiber-based treatments were not considered more effective than placebo, despite a similar OR of 1.83.  Due to the small number of children in these studies with fiber (n=136), the CI were wide: 0.92-3.65.

The authors discuss some of the limitations such as variations in definitions, choice of probiotic and dosage, and short-term duration.  There is not a discussion of selection bias.  It is quite possible that some negative studies were completed which were not published which could further lower or eliminate the potential benefit.

My take: Probiotics may be helpful for children with recurrent abdominal pain; it is certainly not a panacea.

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Is Deamidated Gliadin Serology a Useful Adjunct in Screening for Celiac Disease?

A recent multicenter retrospective study (MJ Gould et al. JPGN 2019; 68: 20-5) shows that deamidated gliadin peptide (DGP) is rarely helpful in screening for celiac disease when tissue transglutaminase IgA is negative. The study identified 40 patients who had a mean age of 6.5 years at time of intestinal biopsy.

Key findings:

  • Of the 40 patients with DGP (IgG) positivity, only 1 patient (2.5%) had celiac disease; this patient was IgA deficient.
  • Among the five IgA deficient patients, only 1 with DGP positivity had celiac disease.
  • The cohort included 6 patients with DGP levels >250 U/mL (refernece <12).
  • Only 5 patients in this DGP positive cohort were younger than 2 years.  None had celiac disease

My take: This retrospective study indicates that DGP is rarely helpful in patients with negative TTG IgA results. However, this study had too few patients who were  <2 years of age and/or IgA-deficient patients to determine its utility in these groups..

Related study: AK Verma et al. JPGN 2019; 68: 26-29. This study from Italy examined oral hygiene products and determined that 62 (94%) were gluten-free (gluten level <20 ppm). Among the 4 with detectable gluten, 3 were toothpastes and 1 lipstick with values between 20.7 adn 35 ppm. My take: Oral hygiene products have very low rates of gluten contamination.

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Blood Test is Better Than a Liver Biopsy for Biliary Atresia

A recent study (L Yang et al. Hepatology 2018; 68: 2069-72) confirms the utility of Serum Matrix Metalloproteinase-7 (MMP-7) as a biomarker for biliary atresia (BA). The authors studied MMP-7 among healthy controls (n=72 with 54 <6 months) and among 135 with cholestasis (75 with BA, 60 with non-BA).  BA samples were taken at a median age of 54 days.

Key findings:

  • Median concentration for MMP-7 was 2.86 ng/mL in healthy controls, 11.47 ng/mL for non-BA cholestasis, and 121.1 ng/mL for BA.
  • Using a cutoff value of 52.85 ng/mL, the diagnostic sensitivity and specificity were 98.67% and 95.0% respectively.
  • The AUC for MMP-7 in BA was 0.99 compared for AUC for GGT of 0.72.  The sensitivity and specificity for GGT was much lower at 64% and 72% respectively with a cutoff of 314 U/L.
  • The predictive value for MMP-7 was particularly impressive, 74 of 75 BA  subjects were correctly identified as having BA.  Only 3 non-BA patients were incorrectly assigned a BA diagnosis based on MMP-7 values.
  • The authors noted that MMP-7 testing indicates that there are no substantial changes in its values for normal subjects extending to 54 years of age.
  • One limitation the authors note is the relatively small number of patients with non-BA syndromatic intrahepatic cholestasis which made up less than 30% of their non-BA cohort.  Thus, more testing in specific populations is needed.

My take: The diagnostic performance of MMP-7** appears to be superior to that of a liver biopsy (though this was not directly compared in this study) in predicting BA and could obviate the need for most liver biopsies in infants with cholestasis.  Those with high MMP-7 values would proceed directly to intraoperative cholangiogram with possible hepatoportojejunostomy. Those with non-BA MMP-7 values and persistent cholestasis could undergo additional investigation with genetic panels and/or other metabolic/infectious testing.

**This assay is likely to be commercially-available in the coming weeks according to a colleague at Cincnnati Children’s Hospital.  The expectation is an approximagely 2-day turnaround.

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NASPGHAN Toolbox App -Review

To all my colleagues and to others who follow this blog, I wish you a happy new year.  Thank you to all of you, especially to those who provide feedback to help improve the content and usefulness.

Recently NASPGHAN released an App, titled NASPGHAN Toolbox.  There are some very useful features but also some areas where more work is needed.

Work in progress: Many of the algorithms that are listed are dated and no longer accurate.  To list a few examples:

  • The UC Algorithm suggests holding off on anti-TNF therapy in severe disease for 7-14 days
  • The EoE Algorithm lists only diet treatments and topical steroids and does not list PPIs as a treatment option
  • The GERD guidelines are from 2001 rather than more recent recommendations

Also, this ‘algorithms’ section should probably be renamed into ‘algorithms and tables’ as a large amount of the information is not algorithmic.

What I Like:

  • Scores and Calculators for items like MELD score, PUCAI score, Mayo score
  • Extensive patient education handouts and image atlas -this could facilitate “airdrop”ing or messaging of these items to families.  (To be picky –the normal esophagus image could be better)
  • Formula charts –though the lists for infants and older children could be more comprehensive
  • Bristol charts (especially children version) -listed in algorithm section

My take: This is a very good start and a very helpful toolbox for pediatric gastroenterologists but I would not rely on the algorithms.


Big Biosimilar Study

Briefly noted: A Meyer et al. Ann Intern Med. 2018. DOI: 10.7326/M18-1512

Abstract link: Effectiveness and Safety of Reference Infliximab and Biosimilar in Crohn Disease: A French Equivalence Study

In this study with 5050 patients, based on review of an administration database, the authors found the following:

  • In multivariable analysis of the primary outcome, CT-P13 (biosimilar) was equivalent to infliximab reference product (RP) (HR, 0.92 [95% CI, 0.85 to 0.99]). 1147 patients in the RP group and 952 patients in the CT-P13 group met the composite end point (including 838 and 719 hospitalizations, respectively).
  • No differences in safety outcomes were observed between the 2 groups: serious infections (HR, 0.82 [CI, 0.61 to 1.11]), tuberculosis (HR, 1.10 [CI, 0.36 to 3.34]), and solid or hematologic cancer (HR, 0.66 [CI, 0.33 to 1.32]).

The authors conclude that “real-world data indicates that the effectiveness of CT-P13 is equivalent to that of RP for infliximab-naive patients with CD.”

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