{
  "abstract": "Introduction EphrinB2 is a transmembrane protein that gets is cleaved into free soluble EphrinB2. It is elevated in fibrosing diseases such as systemic sclerosis (SSc) where it appears to be a key driver of fibrosis via myofibroblast activation. MTX-474 is a humanized IgG1 monoclonal antibody inhibitor of EphrinB2. We hypothesize that MTX-474, via its action on EphrinB2, may promote myofibloblast reversion towards a quiescent state, thus attenuating fibrogenesis and potentially improving skin and internal organs fibrosis in patients with SSc. This first-in-human trial of MTX-474 in healthy volunteers included assessments of safety, pharmacokinetics and target engagement.Material and Methods Healthy volunteers were enrolled into 6 single ascending dose cohorts and 3 multiple ascending dose cohorts. 8 participants were included in each cohort, with 6 randomized to receive MTX-474 and 2 to placebo. MTX-474 was administered in increasing doses via IV infusion to each cohort. Participants were assessed for adverse events, physical exam changes, lab abnormalities, drug exposure levels, immunogenicity, target engagement and exploratory pharmacodynamic biomarkers, in particular Pro-C6 and IL-6.Results MTX-474 appeared safe and well tolerated. Dose escalation was completed through all planned cohorts without difficulty. The most frequent adverse event (AE) was headache, occurring in 61% of MTX-474 treated vs 42% of placebo treated individuals. Other common AEs included fatigue and nausea. There was one serious unrelated AE. Immunogenicity was low with less than 2% of participants (1/54) developing anti-drug antibodies. 100% of participants had quantifiable levels of free EphrinB2 prior to treatment, and treatment with MTX-474 resulted in suppression of free EphrinB2 levels to below the limit of quantitation, indicating target engagement. The duration of suppression of free EphrinB2 in circulation increased with dose culminating in notable suppression over 28 days for a single dose of 4 mg/kg. A trend toward reduction of Pro-C6 ( figure 1), a marker of collagen turnover, and IL-6, a marker of inflammation, was observed at MAD doses that completely suppressed Free EphrinB2 levels.Conclusions MTX-474 appears to be safe and well tolerated with low immunogenicity. It successfully engages it’s target, EphrinB2, and produces a trend toward a reduction in biomarkers associated with fibrosis and inflammation, with the reduced levels of these markers only occurring with doses that completely suppress free EphrinB2 levels.Abstract P.271 Figure 1Change from baseline in pro-C6",
  "authors": [
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Jeffrey Bornstein"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Pablo Zertuche"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Rezi Zawadski"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Colleen Graham"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Chris Espelin"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Kelly Regal"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Daniel Beal"
    },
    {
      "affiliations": [
        "Mediar Therapeutics, Boston, USA"
      ],
      "name": "Paul Yaworski"
    }
  ],
  "title": "P.271 MTX-474 appears safe and well tolerated, engages its target, EphrinB2, and impacts pharmacodynamic biomarkers in healthy volunteers",
  "uid": "3a991b79-012e-513f-8c32-71d435c8d876"
}