Benralizumab reduces eosinophils but does not improve eosinophilic gastritis
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Key takeaways:
- Mean changes in eosinophilic gastritis histology total scores included –0.31 with treatment and –0.02 with placebo.
- Differences in pain intensity, non-pain symptom and satisfaction scores were insignificant.
Treatment with benralizumab induced histological remission, defined as an absence of tissue eosinophilia, among patients with eosinophilic gastritis, according to a study published in The Lancet Gastroenterology & Hepatology.
But the persistence of signs, symptoms and biomarkers of the disease during treatment suggested a pathogenic mechanism independent of eosinophil levels in many patients, Marc E. Rothenberg, MD, PhD, director of the division of allergy and immunology at Cincinnati Children’s Hospital, and colleagues wrote.
Eosinophilic gastrointestinal diseases are thought to be mediated by eosinophils, Rothenberg told Healio.
“We finally tested the role of eosinophils by depleting them from patients,” Rothenberg said.
Rothenberg noted that eosinophilic gastritis impacts the quality of life of patients via chronic symptoms including pain, vomiting and indigestion. The disease also is chronic and debilitating, he said.
Study design, results
The randomized, double-blind, controlled phase 2 trial involved 26 patients (mean age, 19.5 years; 73% male; 96% white) aged 12 to 60 years with symptomatic eosinophilic gastritis, defined as a peak gastric eosinophil count of 30 or more per high-power field (eos/hpf) in at least five hpfs, and blood eosinophilia, defined as more than 500 eosinophils per microliter (eos/µL).
The cohort included 13 patients treated with benralizumab (Fasenra, AstraZeneca) and 13 on placebo, administered subcutaneously once every 4 weeks for 12 weeks. During the open-label extension periods, patients could switch from placebo to benralizumab or continue with benralizumab in two open-label extension periods for up to 88 weeks.
At week 12, 10 of the treatment patients (77%) and one (8%) of the placebo patients had histological remission at week 12 (difference, 69 percentage points; 95% CI, 32-85).
At baseline, the mean peak gastric eosinophil count was 165 eos/hpf (standard deviation, 70). Changes in peak gastric eosinophil counts included means of –137 eos/hpf (95% CI, –186 to –88) for the treatment patients and –38 eos/hpf (95% CI, –94 to 18) for the placebo group through week 12 (P = .008).
Mean changes in eosinophilic gastritis histology total scores included –0.31 (95% CI, –0.42 to –0.2) for the treatment patients and –0.02 (95% CI, –0.16 to 0.12) for the placebo patients (P = .0016).
Histology inflammatory scores included mean changes of –0.46 (95% CI, –0.6 to –0.31) for the treatment patients and –0.04 (95% CI, –0.22 to 0.13) for the placebo group (P = .0006).
Median blood eosinophil counts began with an overall baseline score of 1,350 eos/µL (interquartile range [IQR] = 710-2,630). At week 12, median changes included –1,060 eos/µL (IQR = –1,740 to –830) for the treatment group and –160 eos/uL (IQR = –710 to 120) for the placebo group (P = .0044).
However, the researchers noted, other measurements — including mean changes in eosinophilic gastritis histology structural scores and Eosinophilic Gastritis Endoscopic Reference System scores — did not show any statistically different changes between the groups.
The effect of eosinophil depletion on cardinal features of eosinophilic gastritis pathogenesis was evaluated via transcriptomics. The overall abnormal expression pattern associated with eosinophilic gastritis did not improve with benralizumab. When compared with a reference control group, the expression signature indicated persistent pathology.
The differences in the pain intensity, non-pain symptoms and satisfaction scores in the Severity of Dyspepsia Assessment between the groups were small and not significant, as were the differences between scores in the health domains and pain intensity ratings in the Patient-Reported Outcome Measurement Information System.
Further, the researchers reported that 11 (85%) patients in the treatment group and six (46%) in the placebo group had treatment-emergent adverse events, most commonly headache, nausea and vomiting.
There were two patients with serious adverse events during the open-label extension, but the researchers did not consider these events to be related to the treatment. Also, there were no deaths related to treatment.
Conclusions, next steps
These results, including histological remission in tissue eosinophilia with persisting signs, symptoms and biomarkers of active eosinophilic gastritis in most patients, suggest a pathogenic mechanism independent of eosinophils, the researchers said.
“We found that eosinophils were dispensable without any major clinical benefits,” Rothenberg said, adding that these results were unexpected and “paradigm-shifting.” In fact, Rothenberg said, treatment was ineffective in improving patient well-being.
Physicians should reconsider defining disease remission in eosinophilic gastritis by eosinophil counts alone since core disease features persist once eosinophils have been eliminated, the researchers recommended.
The currently understood paradigm about these diseases as primary eosinophilic disorders may change based on these findings, the researchers continued, as attention shifts from eosinophils as the main contributor to eosinophilic gastrointestinal diseases.
“Monitoring and possibly diagnosing these diseases should shift away from simply counting eosinophils,” Rothenberg said, adding that treatment solely directed against eosinophils likely would not be clinically beneficial.
Successful management of eosinophilic gastritis, the researchers suggested, might require therapies that reduce type 2 inflammation more broadly instead of only targeting eosinophils.
“Therapies that are directed against other components of the disease such as underlying upstream inflammation and non-eosinophil immunocytes should be considered,” Rothenberg said.
For more information:
Marc E. Rothenberg, MD, PhD, can be reached at marc.rothenberg@cchmc.org.
Perspective
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Currently, there are no FDA-approved treatments indicated for eosinophilic gastritis. Current treatment for eosinophilic gastritis involves some trial and error to find what works for a given patient. Treatments may include a combination of dietary restrictions, acid blockers, allergy medications and steroids to reduce inflammation. Patients respond differently to these treatments and long-term steroid use is often required, which can cause significant side effects. Targeted treatments are needed to reduce side effects.
This study is a good initial step in helping to answer important questions about eosinophilic gastritis treatment. As eosinophilic gastritis is a rare disease, the number of patients included in the study was small, which can make it difficult to know if the medication is helpful for some people.
Benralizumab reduced the number of eosinophils in the blood and in the biopsies, as expected. Other measures at 12 weeks were not significantly different in the placebo and benralizumab groups despite the reduction in eosinophils. It is possible a difference may have been found if a larger number of patients had been studied or studied for a longer period of time. It is also possible no difference would be found with more patients or time.
Although not statistically different, the authors found more of a reduction in the symptom score and the EGREF score in the treatment group. A larger trial may be needed to answer the question of benefit more definitively.
I agree with the researchers that these findings suggest that mechanisms beyond eosinophils may be behind eosinophilic gastritis. The immune system is very complicated with intertwined pathways. Additional mechanisms may be causative in eosinophilic gastritis beyond eosinophils alone.
Again, this study helps shed light onto eosinophilic gastritis treatments. It would be interesting to follow the treatment and placebo groups for a longer period of time and to consider other treatments that target other aspects of immune pathways in eosinophilic gastritis. It would be helpful to know what treatments the benralizumab group and the placebo group were on prior to enrollment and what they were taking at the end of the 12 weeks. For example, was the treatment group able to decrease other medications?
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