lirentelimab (AK002) / Allakos - LARVOL DELTA

Emerging IgE and non-IgE targeted therapies for chronic urticaria. (PubMed, Ann Allergy Asthma Immunol) - "Dupilumab received FDA approval for antihistamine refractory chronic spontaneous urticaria (CSU) supporting the targeting of type-2 cytokines, IL-4 and IL-13, in this disease. Bruton's tyrosine kinase (BTK) inhibitors show promise, with remibrutinib receiving FDA approval and demonstrating significant reductions in UAS7 in Phase 3 trials. c-Kit (c-Kit or KIT) inhibition with barzolvolimab shows robust efficacy with sustained effects post-treatment...Although some programs have been discontinued due to safety concerns or lack of efficacy such as fenebrutinib (BTK inhibitor), THB001 (c-Kit inhibitor), EP262 (MRGPRX2 antagonist), tezepelumab (anti- TSLP), as well as lirentelimab and AK006 (Siglec-targeting agents), these studies have informed many of the other positive studies. In summary, over the last year, we have seen the CU pipeline mature with multiple Phase 3 programs and new approvals representing diverse mechanisms of action. Nevertheless, significant..."

Journal • Review • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria • IL13 • IL4 • TSLP

New treatments for systemic mastocytosis in 2025. (PubMed, Curr Opin Allergy Clin Immunol) - "Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results."

Journal • Aggressive Systemic Mastocytosis • CD33 • IL6

Hypereosinophilia: clinical and therapeutic approach in 2025. (PubMed, Curr Opin Allergy Clin Immunol) - "The findings highlight the importance of accurate classification and tailored management of HE and HES, which are crucial for preventing organ damage and improving quality of life. Ongoing clinical trials and research will expand therapeutic options, clarify underlying mechanisms, and address current unmet needs."

Journal • Eosinophilia • Gastrointestinal Disorder • Hypereosinophilic Syndrome • Immunology • Oncology • FIP1L1 • PDGFRA

EXPLORING EMERGING THERAPIES AND TREATMENT PARADIGMS IN EOSINOPHILIC ESOPHAGITIS: A NETWORK META-ANALYSIS (DDW 2025) - "All treatments exhibited statistically significant improvements in HRR (I 2 : 4.61%, T 2 : 0.0959), with Budesonide orodispersible tablets (BOT) showing the highest relative risk (RR: 19.70; Confidence Interval [CI]: 9.54 to 45.98; p < 0.001)...However, Bayesian analysis revealed no significantly superior treatment with high heterogeneity among treatments (I 2 : 99.4%, T 2 : 26.31), and the highest SUCRA value for Lirentelimab at 52.8%...While EREFS results favoring BOT and DSQ results indicate Dupilumab could guide clinical decision-making, the high heterogeneity and the absence of a definitive best treatment option on Bayesian analysis require cautious interpretation of these findings. Further long-term RCTs are necessary to establish more precise treatment efficacy."

Retrospective data • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology

Pharmacologic Treatment of Eosinophilic Esophagitis: Efficacious, Likely Efficacious, and Failed Drugs. (PubMed, Inflamm Intest Dis) - "Before the approval of Jorveza® and Eohilia®, several investigator-initiated randomized controlled clinical studies evaluated esophagus-targeted formulations of either budesonide or fluticasone to treat pediatric and adult EoE patients...Dupilumab (Dupixent®), a monoclonal antibody targeted against IL-4 and IL-13, was approved by regulatory authorities in the USA, Europe, Canada, but not yet Australia...Due to lack of efficacy or unfavorable safety profile, the following drugs are not recommended for EoE treatment: systemic steroids, sodium cromoglycate, montelukast, azathioprine, TNF-antagonists (e.g., infliximab), vedolizumab (mAb against α4β7), benralizumab (mAb against IL-5 receptor), mepolizumab (mAb against IL-5), reslizumab (mAb against IL-5), omalizumab (mAb against IgE), and lirentelimab (mAb against Siglec-8). Long-term effectiveness and safety data on different drugs are currently sparse. Concerted efforts of different stakeholders will be..."

Journal • Review • Eosinophilic Esophagitis • Food Hypersensitivity • Gastrointestinal Disorder • Immunology • Pediatrics • IL13 • IL4 • IL5 • SIGLEC8

Therapeutic Response From Tofacitinib in a Patient with Refractory Multisegment Eosinophilic Gastrointestinal Disorders and Hypereosinophilia (ACG 2024) - "More common therapies EGIDs including elimination diet, PPI, budesonide, and dilation were ineffective, and he failed to respond to omalizumab, benralizumab, vedolizumab, dupilumab, and clinical trial with lirentelimab...This allowed the patient to wean off budesonide while remaining on pantoprazole 40 mg daily and famotidine 40 mg BID...Tofacitinib can induce clinical, endoscopic, and peripheral eosinophilia response and may be considered for patients refractory to other treatments. Further clinical studies are needed to validate its regular use."

Clinical • Asthma • CNS Disorders • Dermatology • Eosinophilia • Eosinophilic Esophagitis • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Hypereosinophilic Syndrome • Immunology • Nephrology • Pain • Psychiatry • Renal Disease • Respiratory Diseases • STAT3

AK006 Drives Mast Cell Anergy as a Result of Antibody Binding Location and Distinct Protein Interaction Network (EAACI 2024) - "Conclusion AK006, inherent to native receptor biology of Siglec-6 combined with optimal epitope selection, has significantly stronger and broader MC inhibitory activity compared to AK002. AK006 has the potential to be a best-in-class MC inhibitor for allergic and chronic inflammatory diseases."

Allergy • Immunology • Inflammation • SIGLEC8

The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs. (PubMed, Int J Mol Sci) - "Currently, the most relevant is dupilumab, which interferes with both interleukin (IL)-4 and IL-13 pathways by binding IL-4 receptor α, and is the only mAb approved by the European Medicine Agency and US Food and Drug Administration for the treatment of EoE. Other mAbs investigated include mepolizumab, reslizumab, and benralizumab (interfering with IL-5 axis), cendakimab and dectrekumab (anti-IL-13s), tezepelumab (anti-TSLP), lirentelimab (anti-SIGLEG-8), and many others. Despite the undeniable economic impact of biologic therapies, in the near future, there will be room for further reflection about the opportunity to prescribe biologic agents, not only as a last-line therapy in selected cases such as patients with comorbidities involving common pathways. Although recent findings are very encouraging, the road to permanent success in the treatment of EoE is still long, and further studies are needed to determine the long-term effects of mAbs and to discover new potential..."

Journal • Review • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology • IL13 • IL4 • IL5

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes. (PubMed, Curr Allergy Asthma Rep) - "Avapritinib and midostaurin can also temper IgE-mediated degranulation...Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM...Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS."

Journal • Review • Oncology • KIT • SIGLEC8

A study of the safety and effectiveness of lirentelimab as a treatment for people with indolent systemic mastocytosis. (PubMed, Br J Dermatol) - No abstract available

Journal

Non-esophageal eosinophilic gastrointestinal diseases: a narrative review. (PubMed, Acta Gastroenterol Belg) - "A recently developed tissue based diagnostic platform which measures differentially expressed genes might be available in the future to classify patients with intermediate eosinophilic tissue levels under the cut-off. For the treatment, corticosteroids are still the cornerstone of treatment but promising research suggests a role of biologicals, such as Lirentelimab (anti-siglec 8) in particular."

Journal • Review • Eosinophilia • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Rare Diseases

An Extension Study of Lirentelimab in Eosinophilic Gastritis and/or Eosinophilic Duodenitis (Formerly Referred to as Eosinophilic Gastroenteritis) (clinicaltrials.gov) - P3 | N=159 | Completed | Sponsor: Allakos Inc. | Active, not recruiting ➔ Completed

Trial completion • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases. (PubMed, Allergy) - "MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects."

Journal • Review • Dermatology • Immunology • Inflammation • Urticaria • CD200 • CD200R1 • SIGLEC8

Comparison of drugs for active eosinophilic oesophagitis: systematic review and network meta-analysis. (PubMed, Gut) - "Although this network meta-analysis supports the efficacy of most available drugs over placebo for EoE treatment, significant heterogeneity in eligibility criteria and outcome measures among available trials hampers the establishment of a solid therapeutic hierarchy."

Journal • Retrospective data • Review • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology

Is lirentelimab the "magic bullet" to fight pathological mast cell activation in systemic mastocytosis? (PubMed, Br J Dermatol) - No abstract available

Journal

Phase 2 Trial in Progress— Lirentelimab in Adults with Moderate-to-Severe Atopic Dermatitis Inadequately Controlled by Topical Treatments (RAD 2023) - P2 | "The results of these studies provide a strong rationale for conducting this phase 2 proof-of-concept, randomized, double-blind, placebo-controlled study of lirentelimab SC in adults with moderate–severe atopic dermatitis inadequately controlled by topical treatments (NCT05155085, "ATLAS"). KEY INCLUSION/CRITERIA: Adults (18-80 years) are eligible for screening if they have had chronic AD presented for ≥3 years with moderate-to-severe symptoms defined as: Eczema Area and Severity Index (EASI) score ≥16, involvement of ≥10% of the Body Surface Area (BSA), and Investigator Global Assessment (IGA) score ≥3, documented recent history of inadequate response to treatment with medications such as topical corticosteroids, calcineurin inhibitors, JAK inhibitors, or PDE4 inhibitors (crisaborole), and biologic-naïve or biologic-exposed (secondary loss of response, intolerance, or lack of access)...STUDY SITES: This study is currently enrolling in the USA and..."

Clinical • P2 data • Allergy • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • SIGLEC8

Allakos Presents Preclinical Data at EAACI Hybrid Congress 2023 Highlighting Lirentelimab and AK006 Mechanisms of Mast Cell Inhibition (BioSpace) - "Allakos Inc...today announced an oral presentation at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress 2023. The presentation highlighted preclinical data detailing lirentelimab and AK006 mechanism of action and inhibitory activity on IgE and non-IgE activated mast cells....Siglec-6 and Siglec-8 interact with numerous activating receptors and signaling molecules in mast cells, including IL-4R⍺, FcεRI, and JAK/STAT, consistent with preclinical data showing that lirentelimab and AK006 inhibit multiple modes of mast cell activation; Siglec-6 interacts with mast cell proteins associated with metabolism and signaling that are not seen with Siglec-8; AK006 inhibits IgE mediated mast cell activation and shows similar IgE inhibitory activity as remibrutinib; AK006 interacts with cell surface KIT and inhibits KIT-mediated mast cell activation..."

Preclinical • Immunology

"@ProfMaurer #EAACI2023 on #Lirentelimab, an anti-sialic acid-binding immunoglobulin-like lectin 8 mAb, selectively inhibits mast cells and depletes eosinophils, in inducible urticaria" (@FlorinDanPopesc)

Dermatology • Immunology • Urticaria

Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial. (PubMed, Br J Dermatol) - P1 | "Lirentelimab was generally well tolerated and improved symptoms and QoL in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM."

Journal • P1 data • Gastrointestinal Disorder • Musculoskeletal Diseases • Pain

Allakos Announces Upcoming Presentation on Lirentelimab and AK006 Mast Cell Inhibition at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid (GlobeNewswire) - "Allakos Inc...today announced an oral presentation at the upcoming European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress 2023. EAACI is being held June 9-11, 2023 in Hamburg, Germany."

Preclinical • Immunology

An Extension Study of Lirentelimab in Eosinophilic Gastritis and/or Eosinophilic Duodenitis (Formerly Referred to as Eosinophilic Gastroenteritis) (clinicaltrials.gov) - P3 | N=159 | Active, not recruiting | Sponsor: Allakos Inc. | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Mar 2023 ➔ Jul 2023 | Trial primary completion date: Mar 2023 ➔ Jul 2023

Enrollment closed • Trial completion date • Trial primary completion date • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder

EoDyssey: A Study of Lirentelimab (AK002) in Patients With Active Eosinophilic Duodenitis (clinicaltrials.gov) - P3 | N=94 | Completed | Sponsor: Allakos Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jul 2022 ➔ Jan 2023

Trial completion • Trial completion date • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder

KRYPTOS: A Study of Lirentelimab (AK002) in Patients With Active Eosinophilic Esophagitis (clinicaltrials.gov) - P2/3 | N=277 | Completed | Sponsor: Allakos Inc. | Active, not recruiting ➔ Completed

Trial completion • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology

ENIGMA 2: A Study to Assess AK002 in Eosinophilic Gastritis and/or Eosinophilic Duodenitis (Formerly Referred to as Eosinophilic Gastroenteritis) (clinicaltrials.gov) - P3 | N=181 | Completed | Sponsor: Allakos Inc. | Active, not recruiting ➔ Completed

Trial completion • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder

An Extension Study of AK002 in Patients With Eosinophilic Gastritis and/or Eosinophilic Duodenitis (clinicaltrials.gov) - P2 | N=58 | Completed | Sponsor: Allakos Inc. | Active, not recruiting ➔ Completed

Trial completion • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder