Granulocyte–macrophage Colony-stimulating Factor (GM-CSF) as a Therapeutic Target in Psoriasis

Randomized, Controlled Investigation Using Namilumab, a Specific Human Anti-GM-CSF Monoclonal Antibody

K.A. Papp; M. Gooderham; R. Jenkins; R. Vender; J.C. Szepietowski; T. Wagner; B. Hunt; B. Souberbielle; on behalf of the NEPTUNE investigators

Disclosures

The British Journal of Dermatology. 2019;180(6):1352-1360. 

In This Article

Abstract and Introduction

Abstract

Background: The relevance of granulocyte–macrophage colony-stimulating factor (GM-CSF) in the management of psoriasis has not been studied previously. GM-CSF is important in the initiation and maintenance of chronic inflammatory processes.

Objectives: To investigate the clinical use of GM-CSF neutralization by evaluating the efficacy and safety of namilumab (AMG203), a monoclonal antibody GM-CSF inhibitor, in patients with moderate-to-severe plaque psoriasis.

Methods: A phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, proof-of-concept study (NEPTUNE) was conducted. Four doses of namilumab (20, 50, 80 and 150 mg, via subcutaneous injection) were compared with placebo. Assessment of the primary end point – the proportion of patients achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75 treatment response) – was performed at week 12. Exploratory investigation at the tissue level was conducted in a subset of the overall study population. The trial was registered with the number NCT02129777.

Results: In total, 122 patients were enrolled and 106 (86·9%) completed the double-blind treatment; 16 (13·1%) prematurely discontinued study medication. Serum concentration–time profiles were as expected for subcutaneous delivery of an IgG1 monoclonal antibody, and exposure increased proportionally with dose elevation. The number of patients showing PASI 75 treatment response at week 12 was low in all groups; no significant difference was recorded in this end point between placebo and any namilumab group. Similar outcomes were recorded for other clinical study end points. Moreover, no significant treatment-related changes from baseline were observed in laboratory investigations of cell types or subpopulations, or cytokines relevant to inflammatory pathways in psoriasis.

Conclusions: GM-CSF blockade is not critical for suppression of key inflammatory pathways underlying psoriasis.

Introduction

Psoriasis is a chronic, immune-mediated inflammatory disease associated with significant impairment of physical and psychological quality of life.[1,2] Present understanding of its pathogenesis places importance on interleukin (IL)-23/IL-17 cytokines and T-lymphocyte activation, with the proinflammatory cytokine IL-17 as the key pathogenic driver.[3]

Recent clinical studies have demonstrated the potential for effective control of psoriasis with specific anti-IL-23 therapy.[4,5] Moreover, systemic IL-17 inhibition[6–8] now appears to offer patients the best therapeutic prospect (speed of onset and overall clinical effect). Despite these treatment advances, investigation of agents with new mechanisms of action is still considered crucial for full characterization of relevant inflammatory pathways and future clinical practice.

As a major immune modulator, granulocyte–macrophage colony-stimulating factor (GM-CSF)[9] is of potential relevance in psoriasis. Within the skin, GM-CSF is produced by activated T lymphocytes, myeloid cells, endothelial cells, macrophages, fibroblasts and keratinocytes.[10,11] It is detectable in psoriasis-related skin blister fluid and in the serum of patients with psoriasis.[12] Its expression is elevated in psoriatic lesions.[13] Supporting a key role in pathogenesis, GM-CSF neutralization in a flaky skin mouse model of psoriasis has been shown to inhibit neutrophil migration to the skin with alleviation of psoriasiform features in the skin.[14] Additionally, GM-CSF treatment of neutropenia in patients with psoriasis can trigger maculopapular eruptions and exacerbation of the disease.[15,16] Together, these features have led to the hypothesis that GM-CSF neutralization in patients with psoriasis could offer clinical benefit through inhibition of keratinocyte proliferation,[17,18] inhibition of cellular infiltration of the skin and key inflammatory cytokines (such as IL-23, IL-12 and IL-17)[19–21] and inhibition of vascularization and angiogenesis.[22]

Namilumab (AMG203) is a human IgG1 monoclonal antibody that potently and specifically neutralizes human and macaque GM-CSF (Takeda: data on file). In the study reported here, the efficacy and safety of namilumab were compared with those of placebo in a 12-week evaluation of treatment for patients with moderate-to-severe plaque psoriasis, providing the basis for a first reported investigation into the relevance of GM-CSF as a therapeutic target for psoriasis.

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