Press Release Details
Kiniksa Presents Preclinical Data on the Role of GM-CSF in GCA at the 2019 ACR/ARP Annual Meeting
- Mavrilimumab suppresses pathogenic immune responses in a validated in vivo model of medium and large vessel vasculitis -
- Additional human ex vivo data support rationale for targeting GM-CSF in GCA -
“The data presented at ACR/ARP further support the mechanistic rationale of targeting GM-CSFRα in patients with GCA,” said
Dr. Cornelia M. Weyand1 and Dr.
Dr. Cornelia M. Weyand presented GM-CSF is a Pro-Inflammatory Cytokine in Experimental Vasculitis of Medium and Large Arteries.
- Data from this validated in vivo model of vasculitis showed that, compared to treatment controls, mavrilimumab, a monoclonal antibody inhibitor targeting GM-CSFRα, reduced tissue inflammation in the arteries.
- In the model, normal human arteries were engrafted into immune-deficient mice. Following the engraftment, peripheral blood mononuclear cells from patients with GCA were transferred to the mice which then caused vasculitis to appear in the normal arteries within 7-10 days.
- After the inflammation had been established, animals were treated with mavrilimumab. Mavrilimumab demonstrated statistically significant reductions in the number of CD3+ T-cells and in innate and adaptive immune responses in the inflamed arteries in addition to significant reductions in key cytokines known to play a role in GCA pathology including interferon-gamma (IFN-γ). These data illustrate that blockade of GM-CSFRα signaling had a strong anti-inflammatory treatment effect.
- The reduced expression of IFN-γ in mice treated with mavrilimumab is of significance for treating GCA as it is the signature cytokine produced by the T helper type 1 (TH1) cell lineage which, along with GM-CSF, has been implicated in multinucleated giant cell formation. The TH1 signature is relatively unresponsive to glucocorticoid therapy and often persists in steroid-treated patients, and is believed to mediate chronic and refractory disease.
Dr. Maria C. Cid presented GM-CSF Pathway Signature Identified in Temporal Artery Biopsies of Patients with Giant Cell Arteritis.
- Data from this study examining human temporal artery biopsies from two independent sources showed the GM-CSF signaling pathway molecular signature was upregulated in GCA biopsies versus control at both the messenger ribonucleic acid (mRNA) and protein level.
- GM-CSF and TH1 pathway signatures (including IFN-γ) were demonstrated in GCA patient temporal arteries by independent analytical techniques. The data also demonstrated active GM-CSF signaling in diseased tissue is evidenced by increased expression of PU.1, a transcription factor downstream of GM-CSF signaling, in the vessel wall.
- Additionally, treatment of ex vivo cultures of GCA arteries with mavrilimumab suppressed expression of these gene products, indicating the biological effect of mavrilimumab on genes relevant to GCA pathophysiology.
Kiniksa is developing mavrilimumab, an investigational fully-human monoclonal antibody that is designed to antagonize GM-CSF signaling by binding to the alpha subunit of the GM-CSF receptor, for the potential treatment of GCA.
GCA is a chronic inflammatory disease of medium-large arteries that causes headaches, jaw and other muscle claudication as well as ischemic visual loss and blindness. Kiniksa estimates U.S. prevalence of approximately 75,000 to 150,000 patients with similar prevalence rates for other major markets.
Kiniksa is enrolling a randomized, double-blind, placebo-controlled, global Phase 2 proof-of-concept clinical trial of mavrilimumab in subjects with GCA in fifteen countries. The primary efficacy endpoint involves measuring GCA flares during the 26-week treatment period. Top-line data are expected in the second half of 2020.
The materials for the presentations are available through the Science section of Kiniksa’s website (www.kiniksa.com).
Mavrilimumab is an investigational fully-human monoclonal antibody that is designed to antagonize GM-CSF signaling by binding to the alpha subunit of the GM-CSF receptor. Kiniksa’s lead indication for mavrilimumab is GCA, a chronic inflammatory disease of medium-large arteries.
Kiniksa is a biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutic medicines for patients suffering from debilitating diseases with significant unmet medical need. Kiniksa has a pipeline of product candidates across various stages of development, focused on autoinflammatory and autoimmune conditions. For more information, please visit www.kiniksa.com.
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions, although not all forward‑looking statements contain these identifying words. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation, statements regarding: our development of mavrilimumab for the potential treatment of GCA; our conclusions from pre-clinical data for mavrilimumab; our expected timing of topline data from our Phase 2 clinical trial of mavrilimumab in GCA; and our estimates of GCA prevalence in
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Source: Kiniksa Pharmaceuticals, Ltd.