prezalumab (AMG 557) / Amgen, AstraZeneca - LARVOL DELTA

Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN-101) Reveals Non-Redundant Roles of T Cell Co-Stimulation Pathways in Systemic Lupus Erythematosus (ACR Convergence 2023) - P2 | " HD or SLE PBMCs were stimulated with artificial antigen presenting cells expressing CD80, CD86, ICOSL and anti-CD3 (OKT3) for 48h with 100 nM of Fc control protein, acazicolcept, or comparators directed against CD28 (abatacept, [CTLA-4-Ig]) or ICOS (prezalumab [anti-ICOSL mAb]) or combined abatacept/prezalumab. Taken together, these and previous findings indicate that simultaneously inhibiting ICOS and CD28 pathways may result in significant disease amelioration in lupus-related inflammation/autoimmunity, with activity superior to agents targeting only one of these pathways. These observations provide further support for the clinical evaluation of acazicolcept for treatment of SLE; a Phase 2 trial of acazicolcept in SLE is ongoing (NCT04835441/Synergy). 1 Ota, M, et al."

IO biomarker • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Rheumatology • Systemic Lupus Erythematosus • CD80 • CD86 • ICOS • IL17A

Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN-101) Reveals Non-Redundant Roles of T Cell Co-Stimulation Pathways in Inflammatory Arthritis. (PubMed, Arthritis Rheumatol) - "Both CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that co-inhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone."

IO biomarker • Journal • Immune Modulation • Immunology • Inflammation • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CD28 • CTLA4 • ICOS

Blocking T cell co-stimulation in primary Sjögren's syndrome: rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers. (PubMed, Clin Exp Rheumatol) - "Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS."

Biomarker • Clinical • IO Biomarker • Journal • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Oncology • Sjogren's Syndrome • T Cell Non-Hodgkin Lymphoma

AstraZeneca: Q3 FY 2016 Results (AstraZeneca) - Anticipated completion of enrollment in P2a (NCT02334306) trial in Sjögren's syndrome in 2017; Anticipated top-line data from P2a trial in Sjögren's syndrome in H1 2017

Anticipated P2a data • Immunology

Prezalumab: Data from P2a trial (NCT02334306) for primary Sjögren's syndrome in Q4 2018 (AstraZeneca) - Q3 2018 Results

P2a data • Immunology

AstraZeneca: Q1 FY 2016 Update (AstraZeneca) - Anticipated top-line results from P1 trial (NCT01683695) in SLE and lupus related inflammatory arthritis in Q2 2016

Anticipated P1 data • Immunology

Sjögren's syndrome: Old and new therapeutic targets. (PubMed, J Autoimmun) - "Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited...While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results..."

Journal • Review • CD40 • IL2

ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Underlying Rheumatoid and Psoriatic Arthritis (ACR-ARHP 2019) - "The immunosuppressive efficacy of dual CD28/ICOS antagonist ALPN-101 is superior to CD28 or ICOS costimulatory pathway inhibitors, administered individually or in combination, in human in vitro and/or mouse in vivo translational studies. The data suggest that ALPN-101 may significantly improve upon the clinical efficacy of currently approved therapeutics like abatacept for treatment of inflammatory diseases, including rheumatoid, psoriatic, and juvenile idiopathic arthritis. A Phase 1 clinical trial with ALPN-101 in healthy volunteers is underway, and trials in inflammatory arthritis and other inflammatory diseases are targeted to begin soon."

IFNG • IL17A • IL1B • IL2 • IL6

ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Associated with Sjögren’s Syndrome (ACR-ARHP 2019) - "The activity of dual pathway inhibition by ALPN-101 was compared to the CD28-only inhibitor abatacept (CTLA-4-Fc) and to the ICOS pathway inhibitor prezalumab (AMG-557; anti-ICOSL, Creative Biolabs). The efficacy of dual CD28/ICOS antagonist ALPN-101 is superior to CD28 or ICOS costimulatory pathway inhibitors, administered individually or in combination, in human in vitro and/or mouse in vivo translational studies. A Phase 1 clinical trial with ALPN-101 in healthy volunteers is underway, in preparation for future trials in multiple autoimmune diseases. Figure 1: ALPN-101 Potently Inhibits T Cell Activation In Vitro in PBMC from Healthy Donors and Sjogren’s Syndrome Patients."

IFNG • IL17A • IL1B • IL2 • IL6

A Phase 2a Study of MEDI5872 (AMG557), a Fully Human Anti-ICOS Ligand Monoclonal Antibody in Patients with Primary Sjögren’s Syndrome (ACR-ARHP 2019) - P2a; "In patients with active pSS, despite decreasing the level of RF, MEDI5872 210 mg did not achieve consistent improvement of clinical or other biomarker measures of disease activity."

Clinical • IO Biomarker • P2a data • PD(L)-1 Biomarker

A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis. (PubMed, Arthritis Rheumatol) - "AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE."

Clinical • Journal