Safety and Efficacy of Long-Term Treatment With Lirentelimab, A Monoclonal Antibody Against Siglec-8, in Patients With Eosinophilic Gastritis and/or Duodenitis

Introduction: Eosinophilic gastritis (EG) and/or duodenitis (EoD) are characterized by chronic gastrointestinal symptoms and accumulation and activation of eosinophils and mast cells in the stomach and/or duodenum. Lirentelimab (AK002), an antibody against siglec-8, depletes eosinophils and inhibits mast cells. In a 16-week randomized, double-blind phase 2 study of patients with moderate–severe EG and/or EoD (ENIGMA), lirentelimab significantly reduced gastrointestinal eosinophils and patient-reported total symptom scores (TSS) compared with placebo. To evaluate the long-term safety and efficacy of lirentelimab, we conducted an open-label extension (OLE) study, and present data by disease type (EG±EoD vs EoD without EG) through week 94. Methods: Fifty-eight of 59 eligible patients, who received 4 monthly infusions of lirentelimab or placebo during the ENIGMA study, entered the OLE study and received up to 26 monthly doses of lirentelimab (0.3 or 1 mg/kg escalating to 3 mg/kg). Abdominal pain, nausea, vomiting, early satiety, loss of appetite, abdominal cramping, bloating, and diarrhea were assessed using a daily electronic patient-reported outcome questionnaire to generate weekly TSS. Patients underwent upper endoscopy with biopsy at screening, week 14 of ENIGMA, and 2 timepoints during the OLE study. Histopathologic analyses were performed by a blinded central pathologist; EG and EoD were defined as ≥30 eos/hpf in ≥5 gastric hpfs and ≥30 eos/hpf in ≥3 duodenal hpfs, respectively. Results: As of March 2021, 13 patients with EG±EoD and 12 patients with EoD without EG received 94 weeks of lirentelimab (ENIGMA+OLE). At week 94, mean TSS was reduced by 70% in patients with EG±EoD and 81% in patients EoD without EG compared with baseline (Table 1). TSS decreased significantly from baseline through week 94 regardless of EG±EoD or EoD without EG (Figure 1). Gastro-duodenal eosinophil counts were significantly reduced. There were no drug-related serious adverse events. The most common adverse events were mild–moderate infusion-related reactions, mostly during the first infusion. Conclusion: In an OLE study, patients with EG±EoD or EoD without EG receiving lirentelimab for up to 94 weeks had sustained and similar reductions in TSS and eosinophil counts in gastric and duodenal biopsies—patients benefited regardless of whether the stomach was involved. Long-term treatment with lirentelimab (AK002) was well tolerated and holds promise for patients with EG and/or EoD.Table 1.: Continued Reduction in Symptoms in Patients Receiving Lirentelimab up to 94 Weeks aTotal lirentelimab exposure, inclusive of the ENIGMA study bUnpaired 2-tailed t test performed on means.Figure 1.: Similar Symptom Responses to Lirentelimab in Patients With EG ± EoD vs EoD Without EG a Total lirentelimab exposure, inclusive of the ENIGMA study b EG ± EoD n = 13, baseline TSS = 34; EoD without EG n = 12, baseline TSS=36 c Fisher exact test performed on proportion of responders ns = not significant.