Biologics in HES and EGPA

Definitions

Although the term “hypereosinophilic syndromes” (HES) was coined by Hardy and Anderson in 1968¹, the first case definition for “idiopathic” HES was not proposed until 7 years later by Chusid, Dale, West and Wolff². In agreement with prior authors, they noted a “continuum of hypereosinophilic disease” with varied clinical manifestations that could be indistinguishable from those in patients with hypereosinophilic disorders of known etiology. These considerations together with the availability of eosinophil-targeted therapeutics prompted the development and refinement of a consensus definition and classification system for all patients with marked peripheral eosinophilia and eosinophil-related disease manifestations.³ Whereas this umbrella definition of HES includes eosinophilic myeloid neoplasms and secondary causes of HES, such as helminth infections and drug hypersensitivity reactions, definitive treatment of these conditions is typically directed at the underlying cause rather than the eosinophilia and data on biologics is sparse. Consequently, this review will exclude myeloid and associated forms of HES, recognizing that there may be a role for eosinophil-lowering biologics in some cases.

Eosinophilic granulomatosis with polyangiitis (EGPA) was first reported in 1951 by Churg and Strauss who described necrotizing granulomatous eosinophilic vasculitis of small to medium arteries in autopsy specimens from 13 patients with polyarteritis nodosa, asthma, sinusitis and eosinophilia.⁴ Over the next several decades, it became apparent that not all patients with what was then called Churg-Strauss syndrome had the classic histopathologic findings. Moreover, definitive documentation of vasculitis was precluded in many patients by the lack of easily accessible tissue and/or treatment with glucocorticoids at the time of presentation. In 1984, Lanham et al. described a characteristic temporal progression of clinical manifestations beginning with a prodromal phase of asthma and/or CRS followed by an eosinophilic phase indistinguishable from HES and ultimately the onset of systemic vasculitis.⁵ These clinical findings became the basis for the first consensus definition of EGPA proposed by the American College of Rheumatology (ACR) in 1990 to distinguish between EGPA and other systemic vasculitides in research studies.⁶ In 2022, new criteria were developed and validated by the ACR and the European Alliance of Associations for Rheumatology (EULAR).⁷ These criteria include the absence of antibodies suggestive of other vasculitides but not the presence of pANCA/anti-myeloperoxidase antibodies identified in 40–50% of patients with EGPA. While these criteria are highly sensitive and specific for the identification of patients with EGPA among patients with small and medium vessel vasculitis, as with the prior criteria, characteristic histopathology is neither required nor sufficient for a diagnosis of EGPA and overlap with other HES is highlighted but not addressed.

As alluded to above, HES can be clinically difficult to distinguish from EGPA. Biomarkers, other than pANCA/anti-myeloperoxidase antibodies, have also proven unhelpful in this regard.^8,9 Further complicating the picture is the fact that eosinophilia, sometimes marked, is a frequent feature of many common diagnoses, including asthma, chronic rhinosinusitis (CRS), and atopic dermatitis, that may be part of HES (i.e., hypereosinophilia is driving the clinical manifestations) or a concomitant condition. This overlap between HES and EGPA is highlighted by the similarities in the criteria used to define these syndromes in recent clinical trials of biologics .^10–12 Although this has generally proven to be a successful strategy, some patients with EGPA (e.g., those with detectable pANCA) or HES (e.g., those with lymphocytic variant) may benefit from biologics that target non-eosinophil pathways or cells. This review will focus on currently available biologics used to treat HES and/or EGPA, including those that are approved for other indications, and a pragmatic approach to their use in these two rare disorders.

Eosinophil-targeted biologics

Interleukin-5 (IL-5) plays a key role in the survival, differentiation, and activation of eosinophils. Thus, the IL-5/IL-5 receptor alpha (IL-5RA) axis is an attractive target for the treatment of both HES and EGPA. Three monoclonal antibodies that bind IL-5 (mepolizumab and reslizumab) or its receptor (benralizumab) are commercially available, and a third (depemokimab, a long-acting anti-IL-5 monoclonal antibody dosed every 6 months), is in clinical trials for the treatment of HES and EGPA (Tables 1–3). Rapid and near complete depletion of blood eosinophils has been reported in response to therapies that bind IL-5 in most patients across clinical indications, but they generally lead to only a moderate (50–60%) reduction in tissue eosinophilia. In contrast, benralizumab has been shown to deplete eosinophils to undetectable (or nearly undetectable) levels in the blood, tissue, and bone marrow.

Table 1.

Research definitions of HES and EGPA

HES			EGPA
Year	Criteria	Ref	Year	Criteria		Ref
1975	a persistent eosinophilia of 1500 eosinophils/mm3 for longer than 6 months, or death before 6 months associated with signs and symptoms of hypereosinophilic disease a lack of evidence for parasitic, allergic, or other known causes of eosinophilia presumptive signs and symptoms of organ involvement	2	1984	asthma peak peripheral blood eosinophil count in excess of 1500/mm3 systemic vasculitis involving two or mor extrapulmonary organs		5
2012	>1500 eosinophils/mm3 on 2 examinations (interval ≥1 month or immediately in the case of life-threatening disease) and/or tissue HE defined by the following: a) percentage of eosinophils in BM section exceeds 20% of all nucleated cells and/or b) pathologist is of the opinion that tissue infiltration by eosinophils is extensive and/or c) Marked deposition of eosinophil granule proteins is found (in the absence or presence of major tissue infiltration by eosinophils). organ damage and/or dysfunction attributable to tissue HE exclusion of other disorders of conditions as major reason for. organ damage	*	1990	At least 4 of the following criteria in a patient with vasculitis: asthma eosinophilia >10% neuropathy, mono or poly pulmonary infiltrates, non-fixed paranasal sinus abnormality extravascular eosinophils		6
2023	≥1500 eosinophils/mm3 on at least two occasions (interval ≥2 weeks)** organ damage and/or dysfunction attributable to tissue HE exclusion of other disorders of conditions as major reason for. Organ damage	3	2022	A score of ≥6 in a patient with small or medium vessel vasculitis:		7
				Obstructive airway disease	+3
				Nasal polyps	+3
				Mononeuritis multiplex	+1
				Blood eosinophil ≥1000/mm3	+5
				Extravascular eosinophil-predominant inflammation on biopsy	+2
				Positive test for pANCA or antiproteinase 3 antibodies.	−3
				Hematuria	−1
Phase 3 clinical trial definition for HES			Phase 3 clinical trial definition for EGPA
>1500 eosinophils/mm3 on 2 examinations (interval ≥1 month or immediately in the case of life-threatening disease) organ damage and/or dysfunction attributable to tissue HE exclusion of other disorders of conditions as major reason for. organ damage			history or presence of: asthma plus eosinophilia blood eosinophil ≥1000/mm3 and/or >10% of leucocytes at least two of the following additional features of EGPA: a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation; neuropathy, mono or poly (motor deficit or nerve conduction abnormality); pulmonary infiltrates, non-fixed; sino-nasal abnormality; cardiomyopathy (established by echocardiography or Magnetic Resonance Imaging); glomerulonephritis (haematuria, red cell casts, proteinuria); alveolar haemorrhage (by bronchoalveolar lavage); palpable purpura; anti neutrophil cytoplasmic anti-body (ANCA) positive (Myeloperoxidase or proteinease 3)

^*Valent P, Klion, AD, Horny, H et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012; 130(3):607–612.e9. doi:10.1016/j.jaci.2012.02.019.

^**Tissue restricted HES can be diagnosed when ≥ 1500 eosinophils/mm³ is not present but one of the following is identified: a) the percentage of eosinophils in bone marrow section exceeds 20% of all nucleated cells, and/or b) a pathologist is of the opinion that tissue infiltration by eosinophils is extensive and/or c) marked deposition of eosinophil granule proteins is found (in the absence or presence of tissue infiltration by eosinophils)

Table 3.

Biologics and EGPA

Biologic	Target	Dose	Boxed warnings	Trial	n	Primary Endpoint	Outcome	Reference
Mepolizumab	IL-5	300 mg every 4 weeks	None	A multicenter, double blind, parallel group, phase 3 trial	136	Total accrued weeks in remission Proportation of participatnts in remission at both weeks 36 and 48	Mepolizumab significantly more accrued week of remission and a higher percentage of participants in remission at noth week 36 and 48	Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 2017;376:1921–32.
Benralizumab	IL-5R alpha	30mg every 4 weeks	None	multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial	140	Remission at weeks 36 and 48	Benralizumab was noninferior to mepolizumab at inducing remission in patient with relapsing or refractory EGPA	Wechsler ME, Nair P, Terrier B, Walz B, Bourdin A, Jayne DRW, et al. Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 2024;390:911–21.
Reslizumab	IL-5	3 mg/kg	Anaphylaxis	Open-label pilot study	10	Oral corticosteroid dose, adverse events, exacerbations, symptom control, disease activity, blood markers, and lung function	Significant reduction in daily oral corticosteroid use (Mean prednisone dose from 17.5 mg to 8.12 mg)	Manka LA, Guntur VP, Denson JL, Dunn RM, Dollin YT, Strand MJ, et al. Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis. Ann Allergy Asthma Immunol 2021;126:696–701.e1.
Depemokimab	IL-5, long-acting	N/A	N/A	Multicenter, randomized double-blind, placebo controlled, phase 3 trial vs. mepolizumab	160	Remission at 36 and 52 weeks	Ongoing	NCT 05263934
Dupilumab	IL-4Rα	Variable	None	Multicenter retrospective; no RCTs	51	N/A	65% had positive response; 35% had AE; 67% had increase in AEC	Molina B, Padoan R, Urban ML, et al. Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study. Ann Rheum Dis. 2023;82(12):1587–1593. doi:10.1136/ard-2023-224756
Tezepelumab	TSLP	N/A	N/A	Phase 2b, multicenter, randomized, double-blinded, placebocontrolled study	66	Clinical remission	Ongoing	NCT 06230354
Rituximab	CD-20	Variable	Fatal infusion reactions; tumor lysis syndrome; severe mucocutaneous reactions; PML	Single-center retrospective; no RCTs	69	N/A	Improvement in 76.8% of patients at 6 months, 82.8% at 12 months and in 93.2% by 24 months; relapses in 54% by 24 months	Teixeira V, Mohammad AJ, Jones RB, Smith R, Jayne D. Efficacy and safety of rituximab in the treatment of eosinophilic granulomatosis with polyangiitis. RMD Open. 2019;5(1):e000905. Published 2019 Jun

Biologics that affect eosinophils without data in treatment of EGPA: Tralokinumab, Cendakimab, Dectrekumab, Bertilimumab, Itepekimab, Tozorakimab

Mepolizumab was the first therapy used in a placebo-controlled trial in patients with HES¹³ and is currently the only biologic with regulatory approval for the treatment of this syndrome. In a landmark phase 2 study, mepolizumab (750 mg iv monthly) was well-tolerated and effective as a glucocorticoid-sparing agent in patients with PDFGRA-negative glucocorticoid-responsive HES,¹³ albeit less effective at reducing eosinophilia in patients with lymphocytic variant HES.¹⁴ In the subsequent open-label extension, 62 of 78 patients were prednisone-free for ≥12 weeks on mepolizumab monotherapy.¹⁵ High dose mepolizumab (750 mg iv monthly) has also been used successfully for the treatment of patients with life-threatening, treatment-refractory disease with complete and partial response rates of 57% and 20%, respectively.¹⁶

The phase III trial that led to the approval of mepolizumab for the treatment of non-myeloid HES in patients ≥12 years of age demonstrated a 50% reduction in clinical flares over a 32 week period in patients with steroid-responsive PDGFRA-negative HES receiving mepolizumab (300 mg subcutaneously monthly) compared to patients in the placebo arm.¹² This effect was irrespective of the baseline eosinophil count, and most patients had undetectable serum IL-5 levels at baseline.¹⁷ As in prior trials, no safety signals were identified. Six symptom domains (abdominal pain/bloating, breathing problems, chills/sweats, muscle/joint pain, nasal/sinus symptoms, and skin symptoms) were assessed using a HES daily symptom questionnaire. In all domains except for skin, patients reported significant improvement on mepolizumab therapy over 32 weeks.¹⁸

Mepolizumab is also effective for the treatment of EGPA and was approved for this indication in adults in 2017. After several open-label trials showed a steroid-sparing effect of mepolizumab (750 mg iv monthly) in patients with EGPA,^19,20 a phase 3 randomized, placebo-controlled trial of mepolizumab (300 mg sc monthly) was conducted in patients with relapsing or refractory EGPA. Mepolizumab therapy led to significantly more weeks of accrued remission (28% vs 3%) and a significantly higher proportion of patients in remission at weeks 36 and 48 (32% vs 3%) compared to placebo.¹¹ Post hoc analyses demonstrated no impact of immunosuppressive therapy, EGPA duration or clinical evidence of a vasculitis phenotype on response rates.^21,22, and clinical benefit was achieved in 78–87% of patients receiving mepolizumab using composite clinical endpoints (compared to 32–52% in the placebo group; p<0.001).²³

Prospective studies of the anti-IL-5 antibody, reslizumab in HES and EGPA have been limited to small open-label case series.^24,25 However, its mechanism of action is identical to that of mepolizumab, and the available data suggest that it is effective in the treatment of patients with these syndromes. Currently approved for the treatment of severe asthma in adult patients with an eosinophilic phenotype,²⁶ reslizumab is administered intravenously using weight-based dosing, a potential advantage for some patients.

Benralizumab is an afucosylated antibody that depletes IL-5RA-bearing cells, of which eosinophils are the major constituent, through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).²⁷ Approved in 2017 for the treatment of severe eosinophilic asthma, benralizumab has shown efficacy in clinical trials in both HES and EGPA. In a placebo-controlled phase 2 trial of benralizumab (30 mg sc monthly) in 20 patients with PDGFRA-negative treatment-refractory HES, 9/10 patients receiving benralizumab had a >50% reduction in AEC at 3 months compared to 3/10 receiving placebo.²⁸ During the open-label phase of the trial, 17/19 evaluable participants experienced hematologic and clinical improvement, that was sustained at 48 weeks in 14 patients²⁸ and for ≥6 years in 10 patients.²⁹ Of note, both patients with JAK2 mutations failed to respond, and all 6 patients with LHES relapsed after an initial response.^28,29 A phase 3 trial of benralizumab in HES is ongoing (NCT04191304).

After an open-label pilot study of benralizumab in EGPA demonstrated efficacy in 10 patients with a >50% reduction of median prednisone dose and reduction in EGPA flares,³⁰ a phase 3, placebo-controlled trial comparing benralizumab to mepolizumab was initiated in adults with relapsing or refractory EPGA. Benralizumab was found to be non-inferior to mepolizumab with similar percentages of patients achieving remission at weeks 36 and 48 (59% vs 56%).¹⁰ Other parameters, including adverse events, time to first relapse and reduction in glucocorticoid dose were also comparable between the two groups. Based on these results, it seems likely that benralizumab will be approved for use in EGPA.

Lirentelimab is a non-fucosylated antibody to siglec-8 (sialic acid-binding immunoglobulin-like lectin 8), a receptor that is expressed on eosinophils, basophils, and mast cells. It has a similar mechanism of action to benralizumab (i.e., induction of antibody-dependent cell cytotoxicity) and has been shown in a placebo-controlled phase 2 trial to deplete eosinophils and basophils in the blood and gastrointestinal tissue of patients with eosinophilic gastritis and duodenitis, including those with peripheral hypereosinophilia.^{63, 31} Unfortunately, lirentelimab did not meet the primary clinical endpoint in a subsequent phase 3 trial in eosinophilic gastroenteritis (NCT04322708) and is not currently in development for the treatment of these or other hypereosinophilic disorders.

Biologics that indirectly impact eosinophils

Eosinophil-trafficking interference.

Eosinophils are primarily tissue-resident cells that migrate from the bone marrow to the blood and finally the tissue, where they may exert pathologic effects in some individuals. Eosinophil migration to the tissue involves interleukins (IL-5), chemokines (eotaxins), chemokine receptors (CCR3) and adhesion molecules (VCAM).³² Interference with any of these may reduce tissue eosinophilia with the potential for concurrent increase in peripheral blood eosinophilia.³³ While no biologics that target eosinophil-trafficking are currently approved for the treatment of HES or EGPA, several are approved for other atopic conditions.^34–38 Biologics in this category target IL-4Ra (dupilumab), IL-13 (tralokinumab, cendakimab, dectrekumab), eotaxin (bertilimumab) and CCR3. Biologics that target IL-5 were discussed previously.

Dupilumab is the best studied and most used biologic that interferes with eosinophil trafficking. It is a fully human monoclonal IgG4 antibody that blocks IL-4Rα and downstream signaling of both IL-4 and IL-13, thus limiting IgE synthesis, Th2 polarization and mucus production. IL-4 and 13 are also critical for VCAM-1 expression and production of eotaxin, effects that contribute to dupilumab’s inhibition of eosinophil migration into inflamed tissues.^32,33,39 This inhibition commonly results in a mild (300–750 cells/μL) and transient (<6 months) increase in peripheral eosinophil count. Eosinophil-related clinical complications of dupilumab therapy due to secondary hypereosinophilia are uncommon^33,34, but do occur.^40–42

Conversely, cases of successful dupilumab treatment of patients with HES or EGPA have been reported,^43–45 and a recent retrospective review of 25 patients with HES and/or EGPA treated with dupilumab with or without a second eosinophil-lowering biologic described a positive clinical response in 82%, although 4/16 patients on dupilumab alone had worsening eosinophilia and associated complications.⁴⁶ Another recent study evaluated dupilumab treatment of 51 patients with EGPA who had refractory upper and lower respiratory symptoms on standard treatment. Although 65% of subjects achieved a partial or complete clinical response, 67% of patients experienced worsening eosinophilia, which was associated with an EGPA flare in 41%.⁴⁷ Dupilumab has not been used in prospective clinical trials in HES or EGPA to date, and there is no published data on the use of other agents that interfere with eosinophil trafficking (i.e., anti-IL-13, anti-eotaxin or anti-CCR3 antibodies) in patients with these disorders.

Upstream alarmin interference.

Upstream alarmins are innate cytokines secreted by epithelial cells in response to tissue injury, and include IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). Alarmins broadly affect allergic inflammation by promoting differentiation of Th2 lymphocytes via effects on dendritic cells and inducing ILC2 cells to release IL-5 and IL-13. They may also promote Th17 lymphocyte differentiation, resulting in neutrophilic inflammation.⁴⁸

Currently, the only approved biologic that targets alarmins is tezepelumab, a fully human IgG2λ monoclonal antibody that binds TSLP and blocks its interaction with the TSLP receptor. Tezepelumab is approved for the treatment of moderate to severe asthma irrespective of endotype.⁴⁹ Whereas no biologics that target upstream alarmins are approved for the treatment of HES or EGPA, tezepelumab is actively being investigated for the treatment of EGPA (NCT06230354). Available clinical data also supports a role for IL-25 and IL-33 in the pathogenesis of allergic inflammation⁵⁰ and vasculitis⁵¹, key features of HES and EGPA; however, neither of the IL-33 antibodies currently in clinical trials (itepekimab and tozorakimab) has received regulatory approval for any indication, and there are no ongoing trials of these agents in HES or EGPA.

B-cell depletion.

In contrast to the previously discussed biologics that target allergic inflammation, rituximab is an anti-CD-20 chimeric monoclonal antibody with broad anti-inflammatory activity through depletion of B-cells. It is routinely used for treatment in several hematologic malignancies and autoimmune diseases (i.e., rheumatoid arthritis, ANCA-associated vasculitis (AAV)). There are no randomized, controlled trials evaluating anti-CD-20 monoclonal antibodies for use in EGPA or HES; however, rituximab has been shown to induce and sustain remission in EGPA, especially ANCA-positive disease, in multiple retrospective and one small prospective study⁵² and is included in the ACR treatment guidelines for severe, active EGPA.⁵³ Data to support the use of rituximab in HES is limited to a single case report.⁵⁴ Caution should be used when using B-cell depleting agents given the risk of humoral immunosuppression, which may persist for extended periods after treatment.⁵⁵

Approach to biologic therapy

Systemic corticosteroids have served as the historical treatment of HES and EGPA. However, recent availability of targeted biologics has provided new avenues to pursue improved outcomes with decreased toxicity. Mepolizumab is the best studied and only biologic agent with regulatory approval for the treatment of non-myeloid HES. Initial treatment depends on the subtype of disease, severity, and consideration of comorbid conditions.^56,57 Dosing for mepolizumab in HES (and EGPA) is 300mg subcutaneously monthly (in contrast to the 100mg monthly dosing approved for asthma and CRSwNP); if treatment failure occurs, an increased dose of 750mg subcutaneously monthly may be effective, as suggested by the early HES and EGPA trials.^13,15 Reslizumab is an intravenous anti-IL5 option if treatment failure occurs in patients with elevated BMI, although there is limited data in HES.^58,25

When initial therapy fails to achieve hematologic remission (AEC <1000 cells/μL) and/or symptom improvement, off-label use of biologic therapy may be considered. In a multicenter, retrospective study evaluating off-label use of biologics in HES, 27 of 39 patients receiving off-label benralizumab, reslizumab, omalizumab, or dupilumab reported improvement in HES symptoms.⁵⁸ As with mepolizumab, patients with lymphocytic variant were less like to respond than patients with idiopathic or overlap forms of HES. Of note, neither dupilumab nor omalizumab treatment led to hematologic remission in this study, although eosinophil suppression was maintained in 56% of patients.

Multiple groups, including ACR and EULAR, have published recent consensus guidelines for the treatment for EGPA.^53,59 The general approach is the same in all of the guidelines. High dose systemic glucocorticoids and either cyclophosphamide or rituximab are recommended for acute life-threatening disease. Whether to use rituximab preferentially for ANCA-positive patients remains controversial.^52,53,59. Systemic glucocorticoids with mepolizumab are considered first-line for active, non-severe EGPA. Alternate regimens include glucocorticoids alone, glucocorticoids with immunosuppressive agents (i.e., mycophenolate or azathioprine), and glucocorticoids with rituximab. Given the results of the recent non-inferiority trial,¹⁰ benralizumab may soon be an additional option for patients with EGPA.

Since asthma and CRS with nasal polyposis are common manifestations of EGPA (and to a lesser degree HES), biologics approved for the treatment of these conditions are often prescribed. Dupilumab is a tempting option in EGPA since patients often experience severe, uncontrolled sinus symptoms, and dupilumab has been shown in one network analysis to have improved efficacy compared to mepolizumab for this indication.⁶⁰ However, dupilumab has been associated with cases of hypereosinophilia and eosinophil-related complications,^40–42,61 and dupilumab efficacy for the treatment of EGPA is mixed.^44–47,58 Theoretically, combination biologic therapy with dupilumab and an eosinophil-lowering biologic could maximize treatment benefit for patients with HES and/or EGPA while limiting potential eosinophil-related adverse events⁴⁶, but current safety and efficacy data are inadequate to advocate this approach. A dual biologic strategy may also be cost prohibitive for many patients.

Biologic agents in development for the treatment of HES and/or EGPA include depemokimab and tezepelumab. Given the success to date with mepolizumab, it is anticipated that depemokimab will be effective in both HES and EGPA and allow more convenient dosing (every 6 months) and the potential for reduced cost over time. Tezepelumab is an intriguing treatment option, particularly for EGPA, given that it limits both T2 and Th17 inflammation, the latter of which may be prominent in EGPA and is not directly inhibited by currently available biologics.^48,62 As the number of commercially available biologics that directly or indirectly target eosinophilic inflammation continues to increase, good quality clinical trial data upon which to base treatment algorithms is a major unmet need.

Table 2.

Biologics and HES

Biologic	Target	Dose	Boxed warnings	Trial	n	Primary Endpoint	Outcome	Reference
Mepolizumab	IL-5	300mg every 4 weeks	None	Multicenter, randomized double-blind, placebo controlled, phase 3 trial	108	Proportion of patients with 1 or more flares of disease during study period of 32 weeks	Mepolizumab decreased the number of patients experiencing 1 or more flares by 50% compared to placebo (28% vs 56%)	Roufosse F, Kahn J-E, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol 2020;146:1397–405.
Benralizumab	IL-5R alpha	30mg every 4 weeks	None	Randomized, double-blind, placebo controlled, phase 2 trial	20	Reduction of at least 50% in absolute eosinophil count	90% of patient in the treatment arm vs 30 % of participants in the placebo group achieved suppression of blood eosinophils. In the open extension, all 17 patients that had hematological response reported clinical improvement	Kuang FL, Legrand F, Makiya M, Ware J, Wetzler L, Brown T, et al. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. N Engl J Med 2019;380:1336–46.
Reslizumab	IL-5	1mg/kg every 4 weeks	Anaphylaxis	Pilot phase 1/2 single-dose study	4	Reduce of eosinophilia and evidence of clincal improvement	Fall in eosinophil counts to normal range in 50% of patient by 48 hours with clinical improvement	Klion AD, Law MA, Noel P, Kim Y-J, Haverty TP, Nutman TB. Safety and efficacy of the monoclonal anti-interleukin- 5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004;103:2939–41.
Depemokimab	IL-5, long-acting	N/A	N/A	Multicenter, randomized double-blind, placebo controlled, phase 3 trial	120	Frequency of flares	Ongoing	NCT 05334368
Dupilumab	IL-4Rα	N/A	None	Retrospective; no RCTs	9	N/A	6 subjects with I-HES had clinical response; 2 subjects with LHES did not have clinical response; 1 subject with overlap HES with clinical response	Chen MM, Roufosse F, Wang SA, et al. An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes. J Allergy Clin Immunol Pract. 2022;10(5):1217–1228.e3. doi:10.1016/j.jaip.2022.02.006

Biologics that affect eosinophils without data in treatment of HES: Tezepelumab, Tralokinumab, Cendakimab, Dectrekumab, Bertilimumab, Itepekimab, Tozorakimab

Key points:

• Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations.

• Biologics that directly or indirectly target eosinophils have provided new avenues for treatment, improving outcomes, and decreasing toxicity.

• Eosinophil-targeted therapies are the best studied biologics for HES and EGPA, are well-tolerated, and offer significant clinical benefit for many patients.

Synopsis:

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations. Historically, the mainstay of therapy for both conditions has been systemic glucocorticoids, However, recent availability of biologics that directly or indirectly target eosinophils has provided new avenues to pursue improved outcomes with decreased toxicity. In this chapter, we summarize the evidence supporting the use of specific biologics in HES and/or EGPA and provide a framework for their clinical use in patients.

Clinics Care Points –

• Mepolizumab is approved for the treatment of both HES and non-severe EGPA and is considered the first line biologic therapy for these disorders.

• The choice of second line biologic in the case of mepolizumab treatment failure or intolerance should be based on disease features and comorbid conditions.

• Dupilumab has shown efficacy in improving symptoms in patients with EGPA and HES but should be used with caution due to the risk for eosinophil-related complications.