Identifying LIGHT as a Potential Target

Data indicate a strong association between a mutation in the gene encoding for the immunomodulator decoy receptor 3 (DcR3) and Crohn’s disease. Our research on the functional consequences of DcR3 mutations identified the cytokine LIGHT as a potential primary target. We built upon this research by engaging experts from academic research institutions, including the Children’s Hospital of Philadelphia (CHOP), before investing in this hypothesis.

Establishing the Utility of LIGHT as a Biomarker.

We proceeded to assess LIGHT levels in pediatric patients with active Crohn’s disease compared with age- and sex-matched healthy controls and showed that plasma LIGHT levels were significantly elevated in 83% of the patients with Crohn’s disease. These data, along with data from preclinical experimental models, established LIGHT as a credible biomarker for Crohn’s disease and a promising molecular target for treatment.

_{*Determined by Mann-Whitney U test. Plasma samples from CHOP Biobank.}

Validating the Clinical Hypothesis

We initiated a phase 1, open-label, proof-of-concept study of AVTX-002 in patients with moderate to severe Crohn’s disease in whom treatment with an approved anti–tumor necrosis alpha (TNFα) monoclonal antibody had failed. Preliminary results show that treatment with AVTX-002 resulted in a rapid decrease in LIGHT levels and improvement in symptoms, including clinically meaningful endoscopic healing. AVTX-002 was well tolerated, with no serious adverse events.

AVTX-002: Rapid Decrease in LIGHT Levels and Clinically Meaningful Endoscopic Healing

^{*SES-CD, Simple Endoscopic Score for Crohn’s Disease.}

Identifying LIGHT as a Potential Target

In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, resulting in the COVID-19 (coronavirus infectious disease 2019) pandemic. Two separate research publications had established the critical role of LIGHT in the progression of ARDS, a primary cause of death from COVID-19 infection. With research into AVTX-002 already underway for treatment of IBD, we evaluated the potential of LIGHT as a treatment target for COVID-19–induced ARDS to address this worldwide public health crisis.

Establishing the Utility of LIGHT as a Biomarker

Assessment of LIGHT levels in patients hospitalized with COVID-19 ARDS compared with healthy controls showed that elevated LIGHT levels were associated with COVID-19 ARDS, with a significant association between elevated LIGHT and mortality in patients ≥60 years of age. These data confirmed LIGHT as a central driver of COVID-19–related cytokine storm and a credible biomarker for COVID-19 ARDS.

Validating the Clinical Hypothesis

We quickly mobilized to establish proof-of-concept for AVTX-002 in the treatment of cytokine storm–induced COVID-19 ARDS. In a phase 2 study of patients hospitalized with COVID-19 ARDS, treatment with AVTX-002 in addition to standard of care at the treatment site resulted in a rapid decrease in LIGHT levels and reduced risk of respiratory failure and mortality. AVTX-002 was well tolerated, with no serious adverse events.

AVTX-002: Significant Reduction in Respiratory Failure and Mortality

Efficacy was greatest in patients aged ≥60 years, the population most vulnerable to severe complications and death from COVID-19 infection.