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.
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 clinical trial is expected to enroll subjects with new-onset and refractory disease. Subjects will be randomized 3:2 to 150 mg of mavrilimumab or placebo injected subcutaneously once every 2 weeks and coadministered with a corticosteroid taper. Treatment duration is 26 weeks, and the primary efficacy endpoint is time to first flare. Topline data are expected in the second half of 2020.
COVID-19 Pneumonia and Hyperinflammation
Thirteen non-mechanically ventilated patients with severe COVID-19 pneumonia and hyperinflammation were treated with a single intravenous dose of mavrilimumab in an open-label treatment protocol. Twenty-six contemporaneous non-mechanically ventilated patients with severe COVID-19 pneumonia and hyperinflammation and with similar characteristics upon admission, including comorbidities, baseline inflammatory markers and respiratory dysfunction, were evaluated as a control-group. All patients in the treatment protocol received optimum local standard of care, including protease inhibitors and antiviral therapies.
Over the course of a 14-day follow-up period, mavrilimumab-treated patients experienced greater and earlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorter hospitalizations, and no deaths. Mavrilimumab was well-tolerated in all patients, without infusion reactions.
Kiniksa is engaged with the U.S. Food and Drug Administration (FDA) and is preparing for a potential registrational development program for mavrilimumab in COVID-19 pneumonia and hyperinflammation. In parallel, academic investigators in the U.S. and Italy are planning investigator-initiated placebo-controlled studies.
The treatment protocol with the investigational drug mavrilimumab was a prospective, interventional, single-active-arm, single-center pilot experience in Italy. It was conducted by Professor Lorenzo Dagna, MD, FACP, Head, Unit of Immunology, Rheumatology, Allergy and Rare Diseases IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University in Milan, Italy within a COVID-19 Program directed by Professor Alberto Zangrillo, Head of Department of Anesthesia and Intensive Care of the Scientific Institute San Raffaele Hospital and Università Vita- Salute San Raffaele in Milan, Italy.
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.
We have a clinical collaboration with Kite, a Gilead Company, to conduct a Phase 2, multicenter study of mavrilimumab in combination with axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. The objective of the study is to determine the effect of mavrilimumab on the safety of axicabtagene ciloleucel. Preclinical evidence shows the potential for interruption of GM-CSF signaling to disrupt chimeric antigen receptor T cell (CAR T)-mediated inflammation without disrupting anti-tumor efficacy. The Phase 2 trial is expected to commence in the second half of 2020.