obexelimab (ZB012) / Xencor, Zenas BioPharma, BMS - LARVOL DELTA

A Study of Obexelimab in Patients With Relapsing Multiple Sclerosis (MoonStone) (clinicaltrials.gov) - P2 | N=93 | Recruiting | Sponsor: Zenas BioPharma (USA), LLC | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Multiple Sclerosis

A Study of Obexelimab in Patients With Relapsing Multiple Sclerosis (MoonStone) (clinicaltrials.gov) - P2 | N=93 | Not yet recruiting | Sponsor: Zenas BioPharma (USA), LLC

New P2 trial • CNS Disorders • Multiple Sclerosis

SunStone: A Study of Obexelimab in Patients With Systemic Lupus Erythematosus (clinicaltrials.gov) - P2 | N=190 | Not yet recruiting | Sponsor: Zenas BioPharma (USA), LLC

New P2 trial • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

POPULATION PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES OF OBEXELIMAB IN HEALTHY VOLUNTEERS AND IN PATIENTS WITH RHEUMATOID ARTHRITIS OR IgG4-RELATED DISEASE (EULAR 2024) - "The population PK analysis of obexelimab demonstrates the ethnic insensitivity of obexelimab PK. Optimal PK, robust RO and PD following 250 mg SC weekly further supports clinical development of obexelimab to treat B-cell mediated autoimmune diseases."

Clinical • PK/PD data • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD19

OBEXELIMAB INHIBITS BCR SIGNALLING AND PATHOGENIC B CELL CHEMOTAXIS IN PATIENTS WITH IGG4-RELATED DISEASE (EULAR 2024) - "Collectively, these gene expression and chromatin accessibility data suggest that obexelimab has a broad inhibitory effect on B cells consistent with the role of phosphoinositides in regulating the cellular and activation mechanisms in B cells. Paired with the previous published data demonstrating interference with BCR signalling, obexelimab likely dampens crosslinked BCR-induced BTK phosphorylation in antigen-experienced B cell subsets from IgG4-RD patients and impacts phosphoinositide mediated B cell migration. Together, these two mechanisms may eliminate the potential of pathogenic, self-reactive B cells to respond to self-antigen, migrate out of secondary lymphoid organs, and infiltrate inflamed tissues."

Clinical • IO biomarker • Inflammation • CD27

Obexelimab in IgG4-related disease: B-cell inhibition as a novel therapeutic approach. (PubMed, Lancet Rheumatol) - No abstract available

Journal • Inflammation

Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial. (PubMed, Lancet Rheumatol) - P2 | "All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease."

Journal • P2 data • Allergy • CNS Disorders • Dermatology • Immunology • Infectious Disease • Inflammation • Musculoskeletal Diseases • Rheumatology • CD19 • CD4 • FCGR2B

IgG4-related disease: A proteiform pathology with frequent chest manifestations (PubMed, Rev Mal Respir) - "Substantial progress has been made over recent years in understanding IgG4-RD pathophysiology, and personalized patient care seems to be an achievable medium-term goal."

Journal • Review • Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pancreatitis • Pulmonary Disease • Respiratory Diseases • BTK • SLAMF7

A Study of Obexelimab in Patients With Warm Autoimmune Hemolytic Anemia (SApHiAre) (clinicaltrials.gov) - P3 | N=134 | Recruiting | Sponsor: Zenas BioPharma (USA), LLC | Trial completion date: Dec 2027 ➔ Jun 2026 | Initiation date: Jun 2023 ➔ Sep 2023

Trial completion date • Trial initiation date • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

Obexelimab Inhibits B Cell Activation and May Interfere with B Cell Chemotaxis in IgG4-Related Disease (ACR Convergence 2023) - "Collectively, these chromatin accessibility and transcriptromic data suggest that reciprocal changes in PIP3 and PI(3,4)P2 dependent events induced by obexelimab on B cells alter B cell activation and migration. Paired with the previous published data demonstrating attenuation of BCR signalling, obexelimab not only reduces PIP3-dependent BCR-induced BTK activation in B cells from IgG4-RD patients but could also enhance PI(3,4 )P2 phosphoinositide-mediated B cell migration, possibly causing sequestration of B cells. Together, these two mechanisms may eliminate the potential of pathogenic, self-reactive B cells to respond to self-antigen, migrate out of secondary lymphoid organs, and infiltrate inflamed tissues."

IO biomarker • Inflammation • CD27

Population Pharmacokinetic and Pharmacodynamic Analyses of Obexelimab in Healthy Volunteers and in Patients with Rheumatoid Arthritis or IgG4-Related Diseases (ACR Convergence 2023) - "The population PK analysis of obexelimab demonstrates the ethnic insensitivity of obexelimab PK. Robust RO and PD following 250 mg SC weekly further supports clinical development of obexelimab to treat B-cell mediated autoimmune diseases."

Clinical • PK/PD data • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD19

Antibody based therapeutics for autoimmune hemolytic anemia. (PubMed, Expert Opin Biol Ther) - "The anti-CD20 rituximab, which targets Ab production by B-cells, induces 80% of response in warm type AIHA (wAIHA) and 50-60% in cold agglutinin disease (CAD). Other B-cell targeting MoAbs including ianalumab, povetacicept, and obexelimab are under active study. The anti-CD38 MoAb daratumumab has been used in several reports to target long-lived plasma-cells responsible of AIHA relapse, being effective even in multi-refractory cases. Anti-complement MoAbs will soon change treatment paradigm in CAD; the anti-C1s sutimlimab rapidly increased Hb in more than 80% of cases. Finally, MoAbs inhibiting the neonatal Fc receptor (FcRn), such as nipocalimab, can reduce the half-life of the pathogenic autoAbs, representing a promising treatment for wAIHA...Thus, combination with B-cell/plasma cell targeting drugs will deserve to be explored. On the other hand, their rapid efficacy should be exploited for the acute AIHA phase."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immunology

A Study of Obexelimab in Patients With Warm Autoimmune Hemolytic Anemia (SApHiAre) (clinicaltrials.gov) - P3 | N=134 | Recruiting | Sponsor: Zenas BioPharma (USA), LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

"Obexelimab in IgG4-related disease: B-cell inhibition as a novel therapeutic approach Linked Comment by Tobias Alexander & Gerd R Burmester (@r_burmester) @ChariteBerlin https://t.co/6pQioHYX2O" (@TheLancetRheum)

Gastroesophageal Reflux Disease • Inflammation

Advances in natural products and antibody drugs for SLE: new therapeutic ideas. (PubMed, Front Pharmacol) - "This review discusses the current experience including B-cell targeted drugs (belimumab, tabalumab, blisibimod, atacicept, rituximab, ofatumumab, ocrelizumab, obexelimab, and epratuzumab), T-cell targeted drugs (abatacept, dapirolizumab, and inhibitor of syk and CaMKIV), cytokines targeted drugs (anifrolumab and sifalimumab), and natural products (curcumin, oleuropein, punicalagin, sulforaphane, icariin, apigenin, and resveratrol). The aim of this paper is to combine the existing in vitro and in vivo models and clinical research results to summarize the efficacy and mechanism of natural drugs and targeted drugs in SLE for the reference and consideration of researchers."

Journal • Review • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • SYK

A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial of Obexelimab in Systemic Lupus Erythematosus with Exploration of Response Based on Gene Pathway Co-Expression Patterns. (PubMed, Arthritis Rheumatol) - "Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation."

Journal • P2 data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study of Obexelimab in Patients With Warm Autoimmune Hemolytic Anemia (SApHiAre) (clinicaltrials.gov) - P3 | N=134 | Not yet recruiting | Sponsor: Zenas BioPharma (USA), LLC

New P3 trial • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

INDIGO: A Phase 3 Study of Obexelimab in Patients With IgG4-Related Disease (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: Zenas BioPharma (USA), LLC

New P3 trial • Inflammation

Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in Adult Healthy Volunteers and in Patients with Rheumatoid Arthritis (ACR Convergence 2022) - "Obexelimab PK were similar between adult healthy volunteers and RA patients. Robust RO and PD data at the investigated doses from both studies supported further clinical development of obexelimab to treat B-cell mediated autoimmune diseases"

Clinical • PK/PD data • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD19 • CD20

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies. (PubMed, Neurotherapeutics) - "Controlled trials are needed in IgG4-ND not only with rituximab but also with the other anti-B cell agents that target CD19/20, especially those like obexelimab and obinutuzumab, that concurrently activate the inhibitory FcγRIIb receptors which have low binding affinity to IgG4, exerting a more prolonged anti-B cell action affecting also antigen presentation and cytotoxic T cells. Antibody therapies targeting FcRn, testing those anti-FcRn inhibitors that effectively catabolize the IgG4 antibody subclass, may be especially promising."

Journal • Review • CNS Disorders • Immunology • CD19 • CD20 • CNTN • CNTN1

Zenas BioPharma Acquires Exclusive Worldwide Rights to Obexelimab from Xencor (GlobeNewswire) - "Xencor...and Zenas BioPharma...announced that Zenas has acquired from Xencor exclusive worldwide rights to develop, manufacture and commercialize the investigational antibody obexelimab....Under the terms of the new agreement, Zenas will issue to Xencor a warrant giving Xencor the right to acquire additional Zenas equity, such that Xencor’s total equity in Zenas would be 15% of its fully diluted capitalization following the closing of Zenas’ next round of equity financing, subject to certain requirements."

Licensing / partnership • Immunology • Lupus

Emerging B-Cell Therapies in Systemic Lupus Erythematosus. (PubMed, Ther Clin Risk Manag) - "This review discusses the current experience with B-cell-targeted therapies, including those targeting B-cell-surface antigens (rituximab, ocrelizumab, ofatumumab, obinutuzumab, obexelimab, epratuzumab, daratumumab), B-cell survival factors (belimumab, tabalumab, atacicept, blisibimod), or B-cell intracellular functions (ibrutinib, fenebrutinib, proteasome inhibitors), for the management of SLE. It focuses on ongoing clinical trials and real-world post-marketing use, where available, including their safety profiles, and concludes with our recommendations for B-cell-centric approaches to the management of SLE."

Journal • Review • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

[VIRTUAL] DISCRIMINATION OF SYSTEMIC LUPUS (SLE) PATIENTS WITH CLINICAL RESPONSE TO OBEXELIMAB (XMAB®5871) BASED ON A PATTERN OF IMMUNOLOGIC MARKERS (EULAR 2020) - "Precision medicine for SLE has been hampered by heterogenous immune signals with variable expression. Clustering of patients by gene co-expression pathways enabled an efficient, hierarchical array that reduplicated results of a prior SLE cohort, suggesting these are not random phenotypes. Of these 7 reproducible SLE subsets, the combination of clusters 3 and 6 distinguished an obexelimab responder population of 27 out of 71 subjects (38%) with high expression of B and T Cell modules and cell activation pathways."

Clinical • Immunology • Lupus • Systemic Lupus Erythematosus

[VIRTUAL] A Novel Biomarker Identifies Systemic Lupus Erythematous (SLE) Patients Who Benefit from Obexelimab (XmAb®5871) Treatment (ACR-ARHP 2020) - "A novel two-gene classifier developed from whole blood transcriptomic data by RNA-sequencing identifies a biomarker positive group of patients with a high baseline resting and stem-like T-cell (CD27+, CD28+ and TCF7+) signature. These cDx+ patients had superior response rates compared to placebo across multiple clinical endpoints, suggesting that adaptive immune responses such as B-cell antigen presentation and/or T-cell costimulation may be key components of obexelimab effects. This exploratory biomarker analysis supports further assessment of the two gene signature as a patient stratification/companion diagnostic strategy in obexelimab clinical development for SLE and other autoimmune conditions."

Biomarker • Clinical • IO biomarker • IO Companion Diagnostic • Immune Modulation • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD19 • CD27 • FOXP3

Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice. (PubMed, J Transl Autoimmun) - "Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb...These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Lupus • CD19