Giant cell arteritis (GCA) is a chronic inflammatory disease of medium-large arteries.
Monoclonal antibody targets granulocyte macrophage colony-stimulating factor receptor alpha (GM-CSFRα) and inhibits the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF).
GM-CSF is a key growth factor and cytokine that can govern the development and function of dendritic cells, monocytes, macrophages, and granulocytes (eg, neutrophils, basophils, and eosinophils).
We estimate that there are approximately 75,000 to 150,000 patients with GCA in the United States.
Orphan Drug designation granted by the US Food and Drug Administration (FDA) for mavrilimumab for the treatment of giant cell arteritis.
We believe that by blocking GM-CSF signaling, mavrilimumab may be able to reverse the course of GCA by upstream targeting of the cell types driving the inflammatory process, a mechanism that is different from currently available therapies.
The Phase 2 trial randomized 70 patients 3:2 to mavrilimumab 150 mg (N=42) or placebo (N=28) biweekly injected subcutaneously, co-administered with a protocol-defined 26-week oral corticosteroid taper. Patients were stratified by new onset (n=35) or relapsing/refractory (n=35) disease.
The primary efficacy endpoint of time-to-first adjudicated GCA flare by Week 26 in all treated patients was statistically significant (Hazard Ratio = 0.38, p=0.0263). There was a 62% lower risk of flare in mavrilimumab recipients compared to placebo recipients.
The secondary efficacy endpoint of sustained remission at Week 26 in all treated patients was also statistically significant. The sustained remission rate was a 33.3 percentage points higher in mavrilimumab recipients (83.2%) compared to placebo recipients (49.9%) (p=0.0038).
While the study was not powered for disease cohorts, there was a consistent trend of efficacy across the new onset and relapsing/refractory cohorts.
Mavrilimumab was well-tolerated; there were no drug-related serious adverse events, and the rates of drug-related treatment-emergent adverse events between mavrilimumab recipients and placebo recipients were similar.
A 12-week washout safety follow-up period is ongoing, and additional analyses of this Phase 2 trial are planned.
COVID-19 Pneumonia and Hyperinflammation
In an investigator-initiated placebo controlled study, 40 patients with severe COVID-19 pneumonia and hyperinflammation were randomized 1:1 to a single intravenous (IV) infusion of mavrilimumab 6mg/kg (n=21) or placebo (n=19) and were followed for at least 60 days. Data showed an early signal of efficacy, with trends toward clinical improvement as well as lower mortality and shorter duration of mechanical ventilation in patients treated with mavrilimumab on top of corticosteroids, including dexamethasone, and/or remdesivir. There was no difference in serious adverse events between mavrilimumab-treated patients and placebo recipients.
Kiniksa is enrolling and dosing the global, randomized, double-blind, placebo-controlled Phase 2 portion of an adaptive design Phase 2/3 clinical trial of mavrilimumab in severe COVID-19 pneumonia and hyperinflammation. Data from the Phase 2 portion of the trial are expected in the first half of 2021.
Corticosteroids are the mainstay for the treatment of GCA, but approximately 50% to 70% of patients are corticosteroid refractory or corticosteroid dependent. Long-term administration of corticosteroids carries significant morbidity, especially in an elderly population such as in those with GCA. The FDA recently approved an inhibitor of IL-6 activity as an adjunct to a corticosteroid taper for the treatment of GCA; however, IL-6 production is downstream of GM-CSF and does not address all of the underlying causes of inflammation.