key: cord-0051226-he6c00i0
authors: Bykerk, Vivian P
title: The efficacy and safety of targeting GM-CSF in arthritis
date: 2020-10-07
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30352-0
sha: 6eaa1254b64fdb89c755b2fe54e3d09d6e23a2ec
doc_id: 51226
cord_uid: he6c00i0

nan

Three randomised controlled trials published in The Lancet Rheumatology evaluate the biology, clinical efficacy, and safety of otilimab, in patients with rheumatoid arthritis 1,2 and hand osteoarthritis. 3 Otilimab is a monoclonal antibody that binds to and blocks granulocyte-macrophage colony-stimulating factor (GM-CSF) from connecting with its receptors that is being developed for treatment of rheumatoid arthritis. It is one of four GM-CSF inhibitors undergoing clinical trials in humans; all are humanised monoclonal antibodies. Mavrilimumab targets the GM-CSF α receptor; whereas otilimab, namilumab, and lenzilumab bind directly to GM-CSF. Lenzilumab is being studied in asthma; whereas, the other three GM-CSF inhibitors have shown efficacy in reducing disease activity and improving pain in patients with rheumatoid arthritis. 4 Targeting GM-CSF is a novel therapeutic approach in rheu matoid arthritis, with all available therapies acting to reduce activity of haematopoietic cells. 5, 6 By contrast, GM-CSF mediates the differentiation of macrophages and granulocytes from myeloid cells and, in turn, dendritic cells. Myeloid cells promote cytokine produc tion, tissue damage, and upregulate chemokine (C-C motif) ligand 17 (CCL17)-a mediator of peripheral nerve sensitisation thus far only seen in animal models. 4 These three proofof-concept trials 1-3 are an exciting advance in the field. Christopher Buckley and colleagues 1 did a phase 2b dose finding study evaluating the clinical effects of five doses of otilimab (22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg) versus placebo. Patients with active rheumatoid arthritis and an inadequate response to at least 12 weeks of methotrexate (222 patients, 37 per group) received weekly subcutaneous injections for 5 weeks, which was reduced to every other week until week 50. Standardised otilimab dosing frequencies were used in all three trials. Patients who did not have the prespecified improve ments in disease activity at week 12 or 24 were transferred to otilimab 180 mg. The primary endpoint of Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP) remission at week 24 was not achieved. However, this goal was unrealistic in the patient population assessed, given that the study was powered to detect a large 30% difference between otilimab and placebo. Patients were also assessed for a range of other clinical outcomes, including 20%, 50%, or 70% improvement in American College of Rheumatology (ACR) core domains, including function, and pain. ACR20 responses were reported in 51%, ACR50 responses in 30%, and ACR70 in 19% of patients.

DAS28-CRP 24-week remission rates ranged from 14% to 19% in patients receiving otilimab, similar to those in other trials of advanced therapies studied in patients with an inadequate response to methotrexate. A high number of patients escaped to the 180 mg dose at 12 and 24 weeks-more so in the 135 mg group-resulting in missing data at weeks 16, 20, and 24, and leaving an apparent efficacy advantage of the 90 mg over 135 mg dosage. Dose response relationships across most dosage groups were as expected. Clinically meaningful, doseresponsive improvements in single, core, composite, and patient reported measures support the efficacy of otilimab in rheumatoid arthritis, warranting further study in phase 3 trials.

Mark Genovese and colleagues 2 did a 22-week mechanistic phase 2a proof-of-concept study of otilimab in 39 patients with rheumatoid arthritis, who met the same eligibility criteria as those included in the study by Buckley and colleagues, 1 to evaluate the effect of 180 mg of otilimab (n=28) versus placebo (n=11) on molecular and cellular biomarkers in GM-CSF signalling pathways and on MRI measured synovitis, erosions, osteitis and oedema, and cartilage loss. Groups were imbalanced in terms of DMARD exposure. During the 10-week treatment period, the only meaningful change was reduced serum concentra tions of CCL17 in the otilumab group compared with the placebo group. A clinically meaningful reduc tion in pain severity scores was also reported with otilumab but not with placebo. Differences in MRI out comes were minimal with overlapping CIs. A trend for reduced synovitis and osteitis was seen early during active treatment but not at 12 weeks after stopping of treat ment. The direction of change in outcomes in this study were consistent with what would be expected given pre clinical models of GM-CSF effects but need to be confirmed in larger trials.

The third study by Georg Schett and colleagues 3 was a 22-week, phase 2a exploratory study of pain and hand function in 44 patients with hand osteoarthritis randomly assigned (22 per group) to receive either otilimab 180 mg or placebo. More patients receiving otilimab had numerical clinically meaningful improvement of Shutterstock maximal pain and pain severity over time; the proportion of patients achieving a 30% or higher reduction in pain was numerically (although not statistically) higher in the otilimab group than the placebo group. Hand function also improved more in the otilimab compared with the placebo group. No change in MRI synovitis scores were observed between the groups. More patients withdrew in the otilimab group; two patients receiving otilimab had a herpes zoster infection and one withdrew because of an unrelated humoral fracture. Of note, in the trial by Buckley and colleagues, 1 three fractures were described in patients receiving otilimab suggesting that GM-CSF might have a role in supporting bone health. GM-CSF inhibitors affect the JAK/STAT pathway, thus additional vigilance regarding herpes zoster events is needed.

Because GM-CSF promotes inflammation, tissue destruc tion, and inflammatory cytokine production, and also activates and promotes the survival of mature mye loid cells (including macrophages, neutrophils, and den dritic cells) in autoimmune inflammatory diseases driven by T-helper-1 and T-helper-17 pathways, reducing its concentrations is expected to do more good than harm. However, GM-CSF might be protective in the gut, it improves myasthenia gravis, and it is used to augment anti tumour vaccines. Thus, safety concerns remain regard ing the risk of impairing immunological responses to vaccines and causing colitis or type I diabetes. Alternatively, GM-CSF might have off target benefits in the lung by slow ing the progression of interstitial fibrosis, as suggested by preclinical data. 5, 6 Reassuringly, a review of cumulative safety data from mavrilimumab randomised controlled trials did not reveal safety signals in terms of infection, malign ancy, pul monary disease, pulmonary alveolar proteinosis, or cardio vascular events attributable to the study drug. However, decreases in neutrophil counts below 3000 per mm³ did occur, but no associated adverse safety events were reported. 7 Efficacy waned in the long-term extension groups from those trials indicating that a higher maintenance dose was needed. Will this be the case for otilimab? Calculated pharma cokinetic and pharma codynamic models described linear pharmaco kinetic trends over tested doses. 8 Of concern, antibody clearance was significantly higher and bioavailability was lower than expected of a typical monoclonal antibody, resulting in lower trough concentrations at steady-state and an elimination half-life of 10 days. For clinically meaningful responses, higher trough con centrations using 150 mg of weekly subcutaneous otilimab would be required to maintain DAS28-CRP low disease activity or remission states. 8 Even higher doses would be required to support every other week main tenance schedules.

Factors affecting peak and trough concentrations and durability of response have implications on efficacy and safety. GM-CSF protects against the development of pulmonary alveolar proteinosis, a rare lung disease. Concerns about pulmonary alveolar proteinosis have been high during development of GM-CSF inhibitors, with attempts to offset this risk by excluding patients with low pulmonary reserve by early intensive pulmonary screening. For tunately, no cases of pulmonary alveolar proteinosis have yet occurred in any of the trials of otilumab or trials of other GM-CSF targeting drugs. 7 Practical issues have emerged from these trials. Will screening with pulmonary function tests be a requirement before using otilimab in future? In these studies, partici pants were excluded if their diffusing capacity for carbon monoxide was less than 60% and forced expiratory volume in 1 second was less than 70% of predicted, but the lung diseases of concern were not speci fied. One patient did have a clinically meaningful decline in pulmonary function, not due to pulmonary alveolar proteinosis, but associated with upper lung fibrosis. All patients with a positive tuberculosis test were also excluded from the trials and no cases of tuberculosis were reported, as such these trials cannot inform the risk of GM-CSF inhibitor exacerbation of latent tuberculosis.

In rheumatoid arthritis it remains unknown whether these drugs are best combined with methotrexate or other conventional synthetic DMARDs, and whether they will be effective in patients with late rheumatoid arthritis who have been unresponsive to multiple previous therapies or in those with pauci-immune synovial phenotypes. 9 Incorporating synovial tissue biomarker research could greatly enhance the understanding of who might best respond to GM-CSF inhibitors. There is more to come not only in rheumatoid arthritis and osteoarthritis but from trials of GM-CSF inhibitors being done in COVID-19, asthma, psoriatic arthritis, and ankylosing spondylitis. 10 VPB has reports personal fees from Amgen, Bristol-Myers Squibb, Sanofi, Regeneron, Pfizer, and UCB; grants to The Hospital for Special Surgery Amgen and Novartis; peer reviewed funding to perform research from National Institutes of Health, Patient-Centered Outcomes Research Institute, and Canadian Institutes of Health Research. None of these are related to studies of GM-CSF or companies developing its inhibitors

Division of Rheumatology, Hospital for Special Surgery

Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a randomised, phase 2b, dose-ranging study

MRI of the joint and evaluation of the granulocyte-macrophage colony-stimulating factor-CCL17 axis in patients with rheumatoid arthritis receiving otilimab: a phase 2a randomised mechanistic study

Anti-granulocyte-macrophage colony-stimulating factor antibody otilimab in patients with hand osteoarthritis: a phase 2a randomised trial

GM-CSF as a therapeutic target in autoimmune diseases

GM-CSF-dependent inflammatory pathways

From Growth Factor to Central Mediator of Tissue Inflammation

Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor α monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis

Exposure-efficacy analysis in DMARD inadequate response rheumatoid arthritis patients treated with GSK3196165 along with methotrexate

A pauci-immune synovial pathotype predicts inadequate response to TNFα-blockade in rheumatoid arthritis patients

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities