{
  "abstract": "Background Tolebrutinib, a brain-penetrant, bioactive, Bruton’s tyrosine kinase inhibitor modulates persistent immune activation, including disease-associated microglia and B-cells, potentially affecting smoldering neuroinflammation, a major driver of disability accumulation. We report results of a phase-3 trial evaluating efficacy and safety of tolebrutinib versus placebo in non-relapsing secondary progressive MS (nrSPMS).Methods HERCULES ( NCT04411641) was a phase-3, double-blind, placebo-controlled, event-driven trial. Participants were 18–60 years old with secondary progressive MS, Expanded Disability Status Scale (EDSS) score 3.0–6.5, documented evidence of disability progression during prior 12-months, no clinical relapses during 24-months before screening. Participants were randomized 2:1 to receive oral tolebrutinib (60mg once daily) or matching placebo. Primary endpoint was time to onset of 6-month confirmed disability progression (CDP). Secondary endpoints included additional measures of disability, MRI, and safety.Results 1131 participants were randomized 2:1 to tolebrutinib (N=754) or placebo (N=377) with well-balanced baseline characteristics (mean age:48.9 years, EDSS score:5.5 [median, 6.0], time since relapsing remitting MS symptom onset:17.3 years, and time since most recent relapse:7.5 years). Tolebrutinib treatment was associated with 31% risk reduction in 6-month CDP versus placebo ( P=0.0026). More participants experienced 6-month confirmed disability improvement with tolebrutinib versus placebo (secondary endpoint). There was a slight increase in adverse events with tolebrutinib, including respiratory infections, compared to placebo. Rare events of high liver enzyme increases were observed with tolebrutinib and occurred within 90-days of treatment start. Additional efficacy and safety data will be presented.Conclusion HERCULES is the first trial to demonstrate a slowing of disability accumulation in people with nrSPMS.",
  "authors": [
    {
      "affiliations": [
        "Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, USA"
      ],
      "name": "Robert J Fox"
    },
    {
      "affiliations": [
        "Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, University of Pennsylvania, Philadelphia, USA"
      ],
      "name": "Amit Bar-Or"
    },
    {
      "affiliations": [
        "The University of British Columbia, Division of Neurology, Vancouver, Canada"
      ],
      "name": "Anthony Traboulsee"
    },
    {
      "affiliations": [
        "Multiple Sclerosis Center, University Hospital San Carlos, Madrid, Spain"
      ],
      "name": "Celia Oreja-Guevara"
    },
    {
      "affiliations": [
        "Queen Mary University London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK"
      ],
      "name": "Gavin Giovannoni"
    },
    {
      "affiliations": [
        "University of Lille, Inserm U1172, CHU Lille, FHU Precise, Lille, France"
      ],
      "name": "Patrick Vermersch"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, USA"
      ],
      "name": "Sana Syed"
    },
    {
      "affiliations": [
        "Sanofi, Bridgewater, USA"
      ],
      "name": "Ye Li"
    },
    {
      "affiliations": [
        "Sanofi, Bridgewater, USA"
      ],
      "name": "Wendy S Vargas"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, USA"
      ],
      "name": "Timothy J Turner"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, USA"
      ],
      "name": "Erik Wallstroem"
    },
    {
      "affiliations": [
        "Translational Neuroradiology Section, National Institutes of Health, Bethesda, USA"
      ],
      "name": "Daniel S Reich"
    },
    {
      "affiliations": [
        "Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "John Parratt"
    }
  ],
  "title": "3591 Tolebrutinib versus placebo in non-relapsing secondary progressive multiple sclerosis: efficacy and safety results from the phase 3 HERCULES trial",
  "uid": "c7e34482-2fa4-5129-b60d-730bd5ca9129"
}