Experts at Cincinnati Children's play key
roles in one trial that supports dupilumab use for children under
12 and another study showing no relief for people taking
benralizumab.
Both studies appear in The New England
Journal of Medicine.
CINCINNATI, June 26,
2024 /PRNewswire/ -- Despite high hopes, a drug that
wipes out the namesake cell type associated with the disease
eosinophilic esophagitis (EoE) doesn't make patients feel better
and doesn't reverse tissue damage in their throats.
Meanwhile, data show that a different drug that had previously
been approved for use in adults and teens with EoE is also safe and
effective for children under 12 who weigh at least 15 kg (about 33
pounds).
The results of these clinical trials—plus an accompanying
editorial—appear in the June 17,
2024, edition of The New England Journal of
Medicine.
"Together, these trials provide exciting advances in our
understanding of, and treatment options for, this increasingly
common and perplexing disease," writes Benjamin Wright, MD, an allergist-immunologist
with The Mayo Clinic in Phoenix,
AZ.
Long-time EoE expert Marc
Rothenberg, MD, PhD, and colleagues at Cincinnati Children's
were deeply involved in both studies.
What is EoE?
This severe form of food allergy occurs in an estimated 180,000
people in the United States,
including at least 21,000 children under 11. For those affected, a
variety of foods can trigger a powerful immune response. Patients
can experience painful throat inflammation, tissue damage, and
difficulty swallowing. When not controlled, the ongoing disruption
to a healthy diet can limit a child's growth and lead to other
complications.
The most distinguishing feature of EoE has been a
well-documented spike in the number of eosinophils – a type of
white blood cell – found in the throat. For many years this surge
of immune cells also was believed to be the primary cause of the
disease.
New findings from the Phase 3 MESSINA clinical trial add to a
body of evidence suggesting otherwise.
Effective but not helpful
This study evaluated a monoclonal antibody treatment called
benralizumab, which has been shown in other studies to be highly
effective at reducing unwanted eosinophils. Somewhat like an
exploding paint capsule making it easier for cops to catch a bank
robber, the antibody binds to eosinophil cells and exposes them to
patrolling natural killer cells.
In fact, this treatment has been approved for treating poorly
controlled asthma because it helps break a feedback cycle of
eosinophil-mediated hyperreaction and mucus production in inflamed
airways. That asthma success inspired many scientists to hope that
benralizumab would become a difference-maker in treating EoE.
But when tested in 211 patients with EoE—ages 12 to 65—people
still experienced inflammation, difficulty swallowing, pain, and
reduced quality of life. This occurred despite more than 80% of
those taking benralizumab showing "near-complete depletion" of
eosinophils in their blood and esophagus. Further, microscopic
exams of tissue samples showed no significant improvement at a
biological level.
"This trial calls into question the clinical relevance of
monitoring EoE for treatment effect solely on the basis of the
degree of eosinophilic inflammation," says Rothenberg. "The
MESSINA study highlights the
importance of research as it was a very reasonable assumption that
eosinophilic esophagitis would be caused by eosinophils. Based on
these new results, we now know that this assumption is primarily
incorrect."
Rothenberg, who directs the Division of Allergy and Immunology
at Cincinnati Children's, served as corresponding author for the
study. Evan Dellon, MD, MPH, with
the University of North Carolina at Chapel
Hill, was co-first author.
Extended approval for dupilumab
Benralizumab targets the activity of interleukin-5 (one of
several proteins involved in our bodies' immune response). But
other research has shown better results against EoE by targeting
two other interleukins at the same time: IL-4 and IL-13.
The US Food and Drug Administration initially approved the drug
dupilumab for treating EoE in 2022, but only for adults and teens.
Based on data from a more recent clinical trial focusing on younger
children, the FDA acted in January
2024 to extend approval to children aged 1 to 12 who weigh
at least 15 kg (about 33 pounds).
The data and related findings that supported that decision also
were published in NEJM on June
27.
To date, dupilumab is the only FDA-approved medication that
precisely treats EoE in children.
Years of research producing results
Rothenberg and Margaret Collins,
MD, Division of Pathology and Laboratory Medicine at Cincinnati
Children's, were co-authors on both studies published in the NEJM.
They have been studying EoE for decades and have been active since
the early days in evaluating both drugs.
Julie Caldwell, PhD, Division of
Allergy and Immunology at Cincinnati Children's, was a co-author on
the benralizumab study.
What's next for doctors, researchers and people with
EoE?
In the short term, Rothenberg says that patients should consider
dupilumab, but not benralizumab, or continue (or return to) other
treatments that have been helpful. Dietary elimination therapy to
avoid offending food triggers has been used for years but can be
tough to follow. Various medications have helped some patients
manage symptoms, including proton-pump inhibitors and steroid
treatments. A few newer approaches are still being studied in other
clinical trials.
Longer term, Rothenberg and other scientists are looking farther
"upstream" from eosinophils in the body's natural cascade of immune
system responses to find other ways to stop, slow, or prevent the
damage caused by EoE.
Until such work produces new options, Rothenberg also recommends
that clinicians rely less upon eosinophil levels as the sole
feature to gauge the severity of EoE. Other tests such as endoscope
exams and collecting tissue samples for microscope analysis appear
more likely to provide meaningful information.
"We need a more relevant biomarker to measure clinical response
in eosinophilic esophagitis," Rothenberg says. "That is certainly
one of our main research goals as we move forward."
About these studies
The MESSINA clinical trial was
supported by AstraZenica. The dupilumab clinical trial was
supported by Sanofi and Regeneron Pharmaceuticals.
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SOURCE Cincinnati Children's Hospital Medical Center